Anti-Epileptics Flashcards
What is epilepsy ?
What is the origin of the word ?
The repeated occurrence of sudden excessive or synchronous discharges in cerebral cortical neurons resulting in a disruption of consciousness, disturbance of sensation, movements, impairment of mental function, or some combination of these.
Origin: Greek epilepsia from epilambanein to ‘seize or attack’ (by Gods or demons).
Define the following :
- epileptic seizure
- epileptic disorder
- seizure
- convulsion
- Epileptic Seizure : seizure resulting from epileptic (excessive and/or hypersynchronous), usually self-limited, activity of neurons in the brain.
- Epileptic Disorder : A chronic neurological condition characterized by recurrent epileptic seizures.
- Seizure : A sudden, short event involving a change in a person’s awareness of where they are or what they are doing, their behaviour or their feelings. May be of varied origin.
- Convulsion : A lay term. One form of physical manifestation of a seizure, involving episodes of excessive, abnormal muscle contractions, usually bilateral, which may be sustained or interrupted.
What is the prevalence of epilepsy in the UK ? - worldwide ?
What are the odds of developing this disorder ? - having a seizure ?
How effective is medication ?
How much does it cost ?
- More than 450,000 people in the UK have epilepsy (~1 per 131).
- Worldwide, around 50 million people have epilepsy.
- One person in 50 will develop epilepsy at some time in their life.
- One in 20 will have a single epileptic seizure.
- Up to 75% achieve full seizure control through medication.
- The NHS spent >£268M on prescriptions for AEDs in 2007.
What are the 2 classes of epilepsy (describe both) ?
- Symptomatic indicates that a probable cause exists.
• cerebrovascular lesions
• perinatal or postnatal trauma
• CNS infections
• tumors
• congenital malformations of the CNS - Idiopathic indicates that no obvious cause can be found.
• usually no other neurological condition
• genetic factors probably responsible
What does the diversity of epileptic disorders reflect ?
- numerous underlying cellular and molecular mechanisms
- different spatial and temporal characteristics of seizures
Why do we need to classify epilepsies ?
• Classification provides information on aetiology, appropriate treatment and prognosis
How do we classify epilepsies ?
• Based on symptoms and the electroencephalogram (EEG)
What are the 2 types of seizures that can occur in epilepsy ?
Partial :
• always start in just one hemisphere of the brain
• may involve a small area or all of a hemisphere
• may progress to secondary generalised seizure
Primary generalized :
• both hemispheres from onset
• may have little warning
• involve loss of consciousness
What can a partial seizure (focal seizure) develop into ?
Simple partial seizure : consciousness preserved
Complex partial seizure : consciousness altered
What are the characteristics of a simple partial seizure ?
- only a small part of the brain is affected
- the person remains conscious - may know they are having a seizure
- may involve motor cortex twitching of one contralateral limb or part of a limb
- may involve sensory cortex an unusual smell, taste or feeling (e.g. pins and needles)
- may develop into other seizures - so termed ‘warnings’ or ‘auras’
What are the characteristics of a complex partial seizure ?
- the person’s consciousness is affected, so they may be confused
- can involve automatic movements (‘spontaneous automatisms’) - fiddling with clothes or objects - mumbling or making chewing movements - wandering about
- may have little or no memory of the seizure
- often occurs in the temporal lobes (‘temporal lobe epilepsy’)
What can simple and complex partial seizures develop into ?
Both of these can only develop into a 2ary generalized seizure.
What happens during a 2ary generalized seizure ?
• partial seizures spread, to involve both hemispheres
of the brain
• person becomes unconscious
• may not be aware that their seizure began as a partial seizure
What may occur during a 1ary generalized seizure ?
Tonic seizure = Sustained increase in muscle contraction
Atonic seizure = Sudden loss of muscle tone
Myoclonic seizure = Sudden involuntary muscle contraction
Tonic-clonic seizure = Sequence of tonic and clonic phases
Absence seizure = Brief interruption of consciousness (involves thalamo-cortical circuits)
How long to seizures last in general ?
What happens in the worst cases ?
• Most seizures are limited in duration
• Prolonged or clustered seizures may develop into non-stop seizures - status epilepticus - seizures follow one another with no intervening periods of normal
neurologic function –> requires hospital treatment to bring the seizures under control.
- generalised convulsive status epilepticus may be fatal.
What is an electroencephalogram ?
• a recording of the electrical activity of the cerebral cortex,
usually through electrodes placed on the scalp
• measures the electrical potentials of cortical neuronal
dendrites near the brain’s surface
What is an interictal spike ?
Where does the word come from ?
Ictus - a sudden event (such as a seizure)
Interictal spike - a brief EEG spike occurring between seizure activity
How can an interictal spike be recorded ?
Via scalp EEG or depth EEG.
What is the cellular marker of an epileptic event ?
How can it be measured ?
- PDS (Paroxysmal Depolarizing Shift) = cellular marker of epileptic event
- can be recorded on brain slices via field recording or intracellular recording
During a PDS, what in the sustained suprathreshold depolarization due to ?
What does this normally cause ?
How does this go wrong during epilepsy ?
• sustained suprathreshold depolarization due to entry of Na+, but also Ca2+
• Ca2+ entry produces K+ channel opening, and a prolonged after-hyperpolarization which serves to terminate the PDS
–> failure of the Ca2+-dependent K+ current appears crucial for the transition from interictal spike to seizure
What are the 3 possible causes of epileptogenesis (shift from normal spikes to PDS) ?
1) changes in intrinsic properties :
↑Ca2+, ↑Na+p, ↓K+ channel activity can promote bursting
2) changes in synaptic efficacy :
↑ EPSPs - excessive activation of NMDARs
↓ IPSPs - loss of GABA mediated inhibition
3) changes in synaptic connectivity :
Changes in circuitry prompted by loss of normal input - eg. Hippocampal sclerosis
What is the effect of PDS ?
How does it affect surrounding tissue ?
- The PDS causes a burst of action potentials in the the cell
- This propagates hyperexcitability to surrounding tissue
Certain mutations can lead to idiopathic epilepsy.
What receptors can be affected by these ?
Specify if these are gain or loss of fct mutations.
Loss of fct mutations for : VGPCs, VGCCs, GABA-ARs
Gain of fct mutations for : VGSCs, nAChR
What does the sodium channel mutation in SCN1B lead to ?
Generalized epilepsy with febrile seizures plus.
What does the potassium channel mutation mutation in KCNQ2, KCNQ3 lead to ?
Benign familial neonatal convulsions.
What is the goal of anti-epileptic drugs (AEDs) ?
How might they work ?
What is their effect ?
What is the goal?
• to dampen neuronal hyperexcitability that leads to or sustains an epileptic attack
How might they work?
• reducing excitation
• enhancing inhibitory influences
What is their effect?
• generally ‘antiseizure’ rather than ‘antiepileptogenic’
In theory, how do AEDs decrease excitation ? - increase inhibition ?
Decrease excitation :
- Decrease activity of voltage-gated Na+ and/or Ca2+
channels
- Decrease efficacy of excitatory synapses
Increase inhibition
- Increase efficacy of inhibitory synapses
- Increase K+ channel activity
What is felbamate ?
How does it work ?
Why is it not used clinically ?
Falbamate = an NMDAR blocker –> acts at Gly site of NMDAR
This drugs is efective experimentally, but is not used clinically because it leads to aplastic anaemia and hepatotoxicity
Can postsynaptic AMPAR antagonists be used as AEDs ?
Name a drug if this is relevant.
- too widespread an effect on basal transmission?
• Perampanel = non-competitive AMPAR antagonist –> in phase III clinical trials
What is lamotrigine ?
And AED that reduces Glu release.
Name 6 families of established AEDs (with one drug belonging to each example).
- Hydantoins –> Phenytoin
- Dibenzapines –> Carbamazepine
- Succinimides –> Ethosuximide
- Barbiturates –> Phenobarbitone
- BDZs –> Diazepam
- Fatty Acids –> Sodium Valproate
Name 3 drugs that decrease the activity of VGSCs.
What property about these drugs is absolutely curcial ?
• Phenytoin
• Carbemazepine
• Valproate
All these frugs ensure voltage and ise-dependant inhibition of Na+ channels
What does it mean for a VGSC blocker to be “use-dependent” ?
Why is this important ?
Use-dependent blockade refers to the ability of a drug to preferentially bind to sodium channels in the inactivated state.
This allows AEDs to block the high-frequency discharge that occurs during a seizure without unduly interfering with the low-frequency firing of neurons in the normal state.
What is ethosuximide ?
How does it work ?
Why is it an AED ?
Ethosuximide = T-type Ca2+ channel blocker (and Na+ channels)
Low-threshold (T-type) calcium channels in thalamic neurons enable burst pattern of firing and are important in generation of normal thalamocortical rhythms
They are involved in the genesis of abnormal spike-wave
discharges that characterize absence epilepsy (AKA ‘Petit Mal’).
Give an example of a drug that blocks GABA metabolism.
Explain how it achieves this.
Valproate = an inhibitor of GABA-transaminase (GABA-T),
the enzyme responsible for the breakdown of the GABA. This leads to an increased amount ofGABA in the brain (valproate also blocks Na+channels).
How can GABA action be potentiated ?
Which classes of drugs allow this ?
• Increasing postsynaptic efficacy of GABA by allosteric
modulation of GABA-ARs
• BDZs - Diazepam, Clonzepam
• Barbiturates - Phenbarbitone (may also directly increase Cl-flux)
Name 7 “newer AEDs”.
- Lamotrigine
- Gabapentin
- Topiramate
- Tiagabine
- Levetiracetam
- Vigabatrin
- Oxcarbazepine
When are newer AEDs recommended ?
The newer AEDs are recommended for those :
• who have not benefited from treatment with the older antiepileptic drugs such as carbamazepine or sodium valproate
or
• for whom the older antiepileptic drugs are unsuitable because:
- there are contraindications to the drugs
- could interact with other drugs (oral contraceptives)
- known to be poorly tolerated
- the person is a woman of childbearing potential
What is the advantage of voltage- and use-dependent inhibitors of Na+ channels such as lamotrigine or topiramate ?
These drugs modify the activity of hyper-excitable cells w/o affecting normal activity.
Which drug can inhibit the membrane transport responsible for GABA uptake ?
Tiagabine –> selective inhibitor of GAT-I (on neurons and glial cells)
How is phenytoin eliminated from the body ?
Explain why its plasma levels must be monitored.
Phenytoin is eliminated through hepatic metabolism by a cytochrome P450 system. This shows saturation or
zero-orderkinetics, so plasma half-life (~20hrs) increases with dose. So phenytoin usually given as a single dose and plasma level monitored.
What dictates the choice of drugs in the treatment of epilepsy ?
Dictated by type of seizure and efficacy but also tolerability –> AEDs are associated with idiosyncratic and dose-related side-effects
These may be particularly important with long-term use.
What will be the drug(s) of choice for a :
- partial seizure
- generalized tonic-clonic seizure
- generalized absence seizure
- statues epilepticus
Partial : Carbemazepine, Valproate, Phenytoin
(Lamotrigine, Gabapentin, Topiramate, Tiagabine)
Generalised Tonic-clonic : Valproate, Carbemazepine
(Phenytoin, Lamotrigine, Topiramate)
Generalised absence : Ethosuximide (Valproate, Clonazepam, Lamotrigine)
Status Epilepticus : Clonazepam
Which AEDs have potential developmental toxicity ?
All established AEDs show some teratogenicity
Major congenital malformations 4-10% - a 2 to 4-fold increase
Particular concern over vaplroate
In women of childbearing potential lamotrigine used instead
