AEDs Flashcards
What happens during a seizure in the brain?
Large groups of neurones are activated repetitively, unrestrictedly and hyper-synchronously, with inhibitory neurones failing
What are the two main classifications of seizures?
Focal (partial) seizures
Generalised seizures
What is a focal seizure?
Where the discharges begin in a localised area of the cortex and symptoms reflect the area affected
What are the types of focal seizures?
Simple focal
Complex focal
Jacksonian (focal motor)
Temporal lobe (feeling of deja vu seizures)
What are the symptoms of a focal seizure?
Abnormal sensations or thoughts
Change in behaviour
An involuntary motor action
What happens in generalised seizures?
Generalised centrally and spread through the whole brain, including the reticular system - immediate loss of consciousness
What are the types of generalised seizures? Symptoms of each?
Absence
-patient stares, eyelids may twitch
Tonic-clonic
- vague warning signs
- body becomes rigid
- tongue is bitten
- incontinence can occur
- clonic phase: generalised convulsion, frothing at mouth, rhythmic jerking of muscles
Myoclonic
-contraction and relaxation of a group of muscles, patient tends to be conscious
Atonic
-patient falls due to sudden loss of muscle tone
What is a seizure?
A convulsion or transient abnormal event from episodic discharge of high frequency electrical activity in the brain
What happens in a complex focal seizure?
The patient loses consciousness
What is status epilepticus defined as?
A single convulsion lasting more than 30 minutes or convulsions occurring back to back with no recovery between them
How can status epilepticus cause harm?
Physical injury relating to a fall/crash
Hypoxia
SUDEP (sudden depth in epilepsy)
Brain dysfunction
Cognitive impairment
Serious psychiatric disease
Difference between primary and secondary epilepsy?
Primary - no identifiable cause (idiopathic)
Secondary - underlying medical condition causes the seizures
Causes of secondary epilepsy?
Brain injury and hypoxia
Pyrexia (common in children, recurrence rare)
Brain tumours - partial focal or secondary generalised
Alcohol, drugs, drug withdrawal
Encephalitis and inflammatory conditions eg cerebral abscess, neurosyphilis
Metabolic abnormalities eg hypocalcaemia, hypoglycaemia, hyponatraemia
Provoked seizures eg photosensitivity
In general, what is epilepsy caused by?
Increased excitatory activity
Decreased inhibitory activity
Loss of homeostatic control
Spread of neuronal activity
How can untreated epilepsy lead to morbidity and mortality?
Status epilepticus Physical injury through a seizure SUDEP Adverse reaction to medication Higher risk of psychiatric disease Cognitive impairment
What treatment is there for epilepsy if drugs are unsuccessful?
Temporal lobectomy
Corpus callosal section - prevents seizures spreading between hemispheres - useful for generalised seizures. Good for control but rarely become seizure-free
Hemispherectomy - for children who have irreversible damage to the whole hemisphere
How do voltage-gated sodium channel blockers prevent seizures?
Bind to internal face of sodium channel when in inactivated state
Act preferentially on neurones causing the high frequency discharge that happens in an epileptic fit whilst not interfering with low frequency neurones in their normal state
How do VGSC blockers act preferentially on high frequency neurones?
Because they depolarise more, so there are more of these neurones in the deactivated state, so the drug can bind to them more
Name some VGSC blockers
Carbamazepine
Phenytoin
Lamotrigine
Absorption, protein binding and half-life of carbamazepine?
Well absorbed
75% protein bound
Linear pharmacokinetics
Initially, half life is 30 hours, however is a strong inducer of CYP450 so increases its own metabolism - reduced to 15 hrs with repeated use
ADRs of carbamazepine?
CNS
- dizziness
- drowsiness
- ataxia
- motor disturbance
- numbness
- tingling
GI - vomiting
CVS
- BP variation
- contraindicated in AV conduction
Rash
Hyponatraemia
Severe bone marrow depression leading to neutropenia
Mnemonic to remember CYP450 enzyme inducers?
PC BRAS Phenytoin Carbamazepine Barbiturates Rifampicin Alcohol (chronic) Sulphonylureas
DDIs of carbamazepine?
Reduces phenytoin, warfarin, corticosteroid and OCP levels
Antidepressants can interfere with its actions
Phenytoin can decrease its binding, increasing carbamazepine’s plasma concentration
Epilepsy types treated with carbamazepine?
Generalised tonic-clonic
All types of partial
Protein binding and half-life of phenytoin?
90% bound
Non-linear pharmacokinetics at therapeutic levels so has a variable half life: 6-24 hours
ADRs of phenytoin?
Dizziness Ataxia Headache Nystagmus Nervousness
Gingival hyperplasia
Hypersensitivity rashes including Stevens-Johnson syndrome
DDIs of phenytoin?
Enzyme inducer
Competitive binding with valproate, NSAIDs, salicyclate to increase its plasma levels, exacerbating non-linear pharmacokinetics
Decreases levels of OCP
Cimetidine increases phenytoin levels
How is phenytoin level monitored?
Use salivary levels as indicator of free plasma levels
When is phenytoin used?
Generalised tonic-clonic
All types of partial
IV in status epilepticus
How does lamotrigine work?
Prolongs VGSC inactivation state (like carbamazepine and phenytoin)
Also is a possible calcium channel blocker, and decrease glutamate release
Half-life of lamotrigine?
24 hours, phase II metabolism
ADRs of lamotrigine
Less marked CNS symptoms but
- dizziness
- ataxia
- somnolence
- nausea
Mild and severe skin rashes
DDIs of lamotrigine?
Can be used as an adjunct therapy with other AEDs
OCP reduces plasma LTG levels
Valproate increases plasma LTG levels due to competitive binding
When is lamotrigine used?
Partial seizures
Generalised
- tonic clonic
- absence
First line AED in epilepsy
Safer in pregnancy
Not in paeds due to increased risk of ADRs
How do drugs causing GABA-mediated inhibition help epilepsy?
Enhance activation of GABA receptors by facilitating GABA-mediated opening of chloride ion channels
Causes an inhibitory effect on neurones by increasing threshold for action potential due to Cl
Makes membrane potential more negative, reducing likelihood of epileptic neuronal hyper-activity
Name some drugs which enhance GABA-mediated inhibition
Valproate sodium
Benzodiazepines
Mechanism of action of valproate sodium?
Increases GABA content of brain by stimulating GABA-synthesising enzymes
Inhibit GABA inactivating enzymes
Is valproate sodium protein bound?
Half-life?
Yes
Half-life of 15 hours with linear PK
ADRs of valproate sodium?
Less severe than other AEDs CNS -ataxia -tremor -weight gain
Hepatic
- increases transaminase effects
- hepatic failure (rarely)
DDIs of valproate sodium?
Antidepressants inhibit its action
Antipsychotics antagonise it by lowering convulsive threshold
Aspirin competitively binds in plasma, increasing free valproate
What monitoring is required with valproate sodium?
Free plasma concentration using salivary levels
Monitor for blood, metabolic and hepatic disorder
When is valproate sodium used?
Partial seizures
Generalised
-tonic-clonic
-absence
Mechanism of action of benzodiazepines?
Act at a distinct receptor site on GABA chloride binding channel
Binding if GABA or BZD enhances eachother’s binding, act as positive allosteric effectors
Increases the chloride current into the neurone, increasing threshold for action potential generation
How much are benzodiazepines absorbed and how much are they protein bound in plasma?
Half-life?
Well absorbed - 90-100%
85-100% plasma protein bound
Linear PK - half-life varies from 15-45 hours
ADRs of benzodiazepines?
Sedation Tolerance with chronic use Confusion and impaired coordination Aggression Dependence and withdrawal with chronic use Abrupt withdrawal seizure trigger Respiratory and CNS depression
How to treat an overdose of benzodiazepines?
IV flumazenil however this may precipitate an arrhythmia or seizure
When and which benzodiazepines are used?
Lorazepam/diazepam - status epilepticus
Clonazepam - absence seizure, short-term use
Side effects limit first line use
What is the first line treatment for generalised seizures?
Valproate sodium
What is the first line treatment for partial seizures?
Carbamazepine
What is the first line treatment for generalised and partial seizures in women of child-bearing age?
Lamotrigine
- less effect on OCP
- fewer teratogenic effects
First line of treatment for status epilepticus?
Basic ABCS
Benzodiazepines (lorazepam)
IV Phenytoin - zero order kinetics means therapeutic levels can be reached more quickly
Also paralysis, sedation, intubation
How can AEDs be teratogenic?
Valproate can cause neural tube defects
Congenital malformations
Facial and digital hypoplasia
Learning difficulties
What can be given with AEDs to reduce the risk of neural tube defects?
Folate supplements
Why is vitamin k given in pregnancy with AEDs?
They can cause vitamin K deficiency so reduces risk of cerebral haemorrhage and coagulopathy
What tests should be done in emergency management of status epilepticus?
Blood glucose U&Es Plasma calcium Blood gases Imaging
