AEDs Flashcards
What is epilepsy?
An episodic discharge of abnormal high frequency electrical activity in the brain, leading to seizures
How is epilepsy diagnosed?
Evidence of recurrent seizures unprovoked by other identifiable causes
What is the prevalence of epilepsy?
0.5-1 in 100
How should epilepsy be viewed?
As a symptom of an underlying neurological disorder (not a single disease entity)
What % of patients have success with epilepsy treatment?
75%
How many sudden deaths per year are caused by chronic epilepsy?
500
What are the 4 mechanisms of epilepsy?
- Increased excitatory activity
- Decreased inhibitory activity
- Loss of homeostatic control
- Spread of neuronal hyperactivity
What are the 2 major classes of seizure?
Partial/Focal
Generalised
How can partial seizures be divided?
Simple or complex
What is status epilepticus?
Seizure prolonged beyond 5 minutes or a series of seizures without a recovery interval
Why is status epilepticus a medical emergency?
If it is untreated it can lead to brain damage or death (SUDEP)
What are some of the physical dangers of severe epilepsy?
Physical injury secondary to seizure (fall, car crash)
Danger to others (see above)
Hypoxia
SUDEP
Varying degrees of brain damage or cognitive impairment
What are some of the dangers of treating epilepsy?
ADRs
What are some of the psychosocial dangers of epilepsy?
Stigma
Loss of livelihood
Loss of driving liscence
Psychiatric disease
What % of epilepsy cases are primary/idiopathic?
65-70%
What can cause secondary epilepsy?
Other disease affecting the brain
Vascular disease
Tumours
What % of epilepsy in the elderly is secondary?
60%
What sensory stimuli can precipitate a seizure?
Flashing lights
Strobes
Other periodic sensory timuli
What brain diseases can precipitate a seizure?
Brain injury Haemorhhage Drugs Alcohol Structural abnormality/lesion
What metabolic disturbances can precipitate a seizure?
Hypoglycaemia
Hypocalcaemia
Hyponatraemia
What infections can precipitate a seizure?
TB
HIV
Cerebral malaria
Meningitis
How can some therapeutic agents precipitate a seizure?
By lowering the fit threshold
What therapeutic agents/drugs can precipitate a seizure?
Polypharmacy
Recreational drug abuse
Alcohol
Missing doses of medication
What are the main therapeutic targets for AEDs?
- Voltage gated sodium channels (blocking)
- GABA mediated inhibition (enhancing)
When are VGSCs active?
Only when the neurone is activated
How do VGSC blockers work?
They bind to the activated/depolarised gate to prevent further propagation of action potentials
What do VGSC blockers reduce?
The probability of high abnormal spiking activity
What happens to the VGSC blockers when the membrane potential is back to normal?
It detaches from the site
Name 3 VGSC bloclers
- Carbamezepine
- Phenytoin
- Lamotrigine
What is the indication for carbamezepine according to NICE/BNF?
-Focal and secondary generalised tonic-clonic seizures,
Primary generalised tonic-clonic seizures
- Trigeminal neuralgia
- Prophylaxis of bipolar disorder unresponsive to lithium
- Adjunct in acute alcohol withdrawal
Tell me about the pharmacology of carbamezepine
Well absorbed
75% bound to protein in the blood
Linear pharmacokinetics
What is the half life of carbamezepine?
30 hours
What dose should carbamezepine for epilepsy be started at in an adult?
100-200mg 1-2 times a day
What is funny about carbamezepines metabolism?
It induces CYP450 but is also metabolised by it, so it affects its own phase one metabolism, how crrraaaazy is that?!?!
What can happen with use of carbamezepine?
Half life reduces to 15 hours
What CNS side effects can carbamezepine have?
Dizziness Drowsiness Ataxia Motor disturbance Numbness Tingling Headache
What GI side effects can carbamezepine have?
GI upset
Vomiting
What CVS side effects can carbamezepine have?
Variations in BP
What other (not CVS, CNS or GI) side effects can carbamezepine have?
Rashes
Hyponatraemia
Rarely - severe bone marrow suppression
When is carbamezepine contraindicated?
- AV node conduction problems
- Hx of bone marrow suppression
- Acute porphyrias
Is carbamezepine safe in pregnancy?
It increases the risk of neural tube defects
Doses should be adjusted to plasma levels
Which drugs are decreased in efficacy due to carbamezepine inducing CYP450?
Phenytoin
Warfarin
Systemic corticosteroids
Oral contraceptives
What other DDIs happen with carbamezepine and phenytoin?
Phenytoin binds to plasma proteins and displaces carbamezepine so CBZ plasma concentration increases (so probs has some other side effects because of that)
How should carbamezepine be monitored?
Dose to effect, and adjust dosing as t1/2 decreases
First check plasma conc after 1-2 weeks of use
What is the indication for phenytoin according to NICE/BNF?
Tonic-clonic seizures , Focal seizures (adults and children)
Prevention and treatment of seizures during or following neurosurgery or severe head injury in adults and children
Status epilepticus
Tell me about the pharmacology of phenytoin
Well absorbed
90% bound to plasma protein
CYP450 inducer (not metabolised by cyp450)
What can cause plasma concentrations of phenytoin to increase?
Competition from other protein bound drugs for binding sites
Why are therapeutic levels of phenytoin hard to manage?
Phenytoin has linear kinetics at subtherapeutic levels, but non-linear at therapeutic levels
What is the half life of phenytoin?
UNPREDICTABLE!!!
6-24 hours
Why is it necessary to titrate the levels of phenytoin?
To achieve a balance between efficacy and side effects, and keeping it within the therapeutic window
What CNS side effects can be experienced with phenytoin?
Dizziness Ataxia Headaches Nystagmus Nervousness
What ADR do 20% of phenytoin users experience?
Gingival hyperplasia
What ADR do 2-5% of phenytoin users experience?
Rashes (hypersensitivity and Stevens Johnson)
What dose should phenytoin for epilepsy be started at in an adult?
3-4mg/kg daily initially
Which other drugs does phenytoin compete for binding sites with in the plasma?
Valproate
NSAIDs
Salicylates (including aspirin)
Which drug is decreased in efficacy with phenytoin, and why?
Oral contraceptive as it is metabolised by CYP450
What does cimetidine do to phenytoin?
Increases plasma concentration (no effect on plasma protein binding), probably by inhibiting its metabolism
How should phenytoin use be monitored?
Free concentration in plasma
What can e used as an indication of free concentration of phenytoin in plasma?
Salivary levels of phenytoin
When is phenytoin contrainidcated?
Acute porphyrias
2nd or 3rd degree heart block
Sino-atrial block
Sinus bradycardia
When should phenytoin be stopped immediately?
If there is hepatotoxicity
What can happen in phenytoin toxicity? (symptoms)
Nystagmus Diplopia Slurred speech Ataxia Confusion Hyperglycaemia
What is the indication for lamotrigine according to NICE/BNF?
Focal seizures
Primary and secondary generalised tonic-clonic seizures
Bipolar Disorder
Tell me about the pharmacology of lamotrigine
Well absorbed
Linear PK
Not a CYP450 inducer
What is the half life of lamotrigine?
24 hours
Why does lamotrgine have fewer DDIs than other VGSC blockers?
It is NOT a CYP450 inducer
Why else is lamotrigine a good VGSC blocker?
It has less marked ADRs
What CNS side effects does lamotrigine cause?
Dizziness
Ataxia
Somnolence
What other side effects can lamotrigine cause?
Mild Nausea (10%) Serious nausea (0-5%) Skin rashes (especially in children)
When is it especially important to monitor drug levels with lamotrigine?
When used in combination therapy with other AEDs
What can decrease the levels of lamotrigine in theblood?
Oral contraceptives
How do valproate and lamotrigine interact?
Valproate increases LTG in blood due to competative binding
What are the potential benefits of lamotrigine over other AEDs?
Potentially safer in pregnancy than other VGSC blockers
What are the 2 ways of enhancing GABA mediated inhibition?
Decreasing GABA metabolism
Binding with GABAa receptors
Which agents bind with GABA a receptors?
Valproate
Benzodiazepines
Which agent decreases GABA metabolism?
Valproate
What % of synapses in the brain are GABA-ergic?
40%
What is the major role of GABA in the brain?
Post-synaptic inhibition
What does this mean increased levels of GABA do?
Act as a natural anticonvulsant and as an excitatory brake
Where do benzodiazepines and barbiturates work?
At different sites (subnits) on the GABA receptor
What is the structure of a GABA receptor?
Cl- channel running between 5 subunits, each with different associated bidning sites
How does binding with a GABA a receptor work as an AED mechanism?
The binding of the drug causes an increased Cl- current through the channel into the neurone so the threshold for an action potential is increased and the resting membrane potential becomes more negative
What are the mechanisms of decreased GABA metabolism?
- Inhibit reuptake
- Inhibit inactivation
- Increase synthesis
Why is valproate considered a “dirty” drug?
It is pleotropic i.e. it acts at multiple sites
Describe the many actions of valproate (breifly)
Weak inhibition of GABA inactivation
Weak stimulus of GABA roduction
VGSC blocker
Weak Ca2+ channel blocker
Tell me about the pharmacology of valproate
100% absorbed
90% bound to plasma
Linear PK
What is the half life of valproate?
15 hours
What is good aboiut valprate for the patient?
The ADRs are generally less severe than with other AEDs
What CNS side effects can valproate have?
drowsiness
ataxia
tremor
What other side effects can valproate have?
Weight gain
Deranged hepatic function (eg increased transaminase)
What inhibits valproate?
Antidepressants! SSRIs, MAOI, TCAs,
How do antipsychotics antagonise valproate?
By lowering the convulsive threshold
How do aspirin and valproate interact?
Compete for binding sites so plasma valproate increases
What is the indication for valproate according to NICE/BNF?
All forms of epilepsy
What is the starting dose for an adult for valproate?
600mg daily (divided into 1 or 2 doses)
What is the deal with pregnancy and valproate?
Valproate is contraindicated in pregnancy as it is teratogenic
Pregnancy should be excluded before starting valproate
An effective contraceptive must be given with valproate in women with child-bearing potential
What is the deal with pregnancy and valproate?
Valproate is contraindicated in pregnancy as it is teratogenic
Pregnancy should be excluded before starting valproate
An effective contraceptive must be given with valproate in women with child-bearing potential
Name some benzodiazepines
Valium
Lorazepam
Diazepam
Clonazepam
When do benzos act?
At a distinct site on the GABA chlorine channel
What effect do GABA and BZDs have on each other?
They enhance the effect of the other
Tell me about the pharmacology of benzodiazepines
Well absorbed (90-100%)
Highly plasma bound (85-100%)
Linear PK
What is the half life of benzodiazepines?
~15-45 hours
When are benzos used, and why?
Usually only in status epilepticus as they have a wide range of ADRs. Not usually first line for epilepsy.
What are some of the ADRs of benzodiazepines?
Sedation Tolerance in chronic use Confusion Impaired coordination Aggression Trigger seizures if withdrawn abruptly Respiratory and CNS depression
How is a benzo overdose treated?
IV flumazenil
What is the problem with flumazenil?
It may precipitate a seizure or arrhythmia
What is the optimal aim when prescribing AEDs?
Monotherapy!
With this in mind, how should epilepsy drugs be started?
Systematically, one at a time, replacing those which are ineffective
What should drug choice be based on?
The individual patient and the seizures they have had
What should be done in pregnancy with epilepsy?
Balance the risk of epilepsy vs the risk to the pregnancy (AED teratogenicity)
What is the failure rate of OCP when combined with AED?
4x higher than normal as metabolism increased (up to 4-8% failure rate). Dose dependant, up to 10%.
What effect can many AEDs have on the foetus?
Facial and digital hypoplasia
General congenital malformation
Which AED is a) the worst in pregnancy, and b) the safest?
a) Valproate
b) Lamotrigine
What can help reduce the risk of neural tube defects with AEDs?
Taking a folate suppliment, ideally prior to conception
What other suppliment should be given to the mother on AEDs, when, and why?
Vitamin K
Third Trimester
Prevents newborn deficiency which leads to coagulopathy and haemorrhage
What are the drugs usually given for status epilepticus in order of priority?
- Benzos (usually lorazepam) - fast acting with good control
- Phenytoin - reaches therapeutic levels quickly IV but cardiac monitoring (zero order kinetics)
- Midazolam/Pentobarbital/Propofol
