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PHAR2005 > Anti-Epileptics > Flashcards

Anti-Epileptics Flashcards

1
Q

What is epilepsy ?

What is the origin of the word ?

A

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).

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2
Q

Define the following :

  • epileptic seizure
  • epileptic disorder
  • seizure
  • convulsion
A
  • 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.
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3
Q

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 ?

A
  • 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.
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4
Q

What are the 2 classes of epilepsy (describe both) ?

A
  • 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
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5
Q

What does the diversity of epileptic disorders reflect ?

A
  • numerous underlying cellular and molecular mechanisms

- different spatial and temporal characteristics of seizures

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6
Q

Why do we need to classify epilepsies ?

A

• Classification provides information on aetiology, appropriate treatment and prognosis

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7
Q

How do we classify epilepsies ?

A

• Based on symptoms and the electroencephalogram (EEG)

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8
Q

What are the 2 types of seizures that can occur in epilepsy ?

A

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

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9
Q

What can a partial seizure (focal seizure) develop into ?

A

Simple partial seizure : consciousness preserved

Complex partial seizure : consciousness altered

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10
Q

What are the characteristics of a simple partial seizure ?

A
  • 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’
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11
Q

What are the characteristics of a complex partial seizure ?

A
  • 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’)
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12
Q

What can simple and complex partial seizures develop into ?

A

Both of these can only develop into a 2ary generalized seizure.

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13
Q

What happens during a 2ary generalized seizure ?

A

• 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

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14
Q

What may occur during a 1ary generalized seizure ?

A

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)

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15
Q

How long to seizures last in general ?

What happens in the worst cases ?

A

• 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.

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16
Q

What is an electroencephalogram ?

A

• 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

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17
Q

What is an interictal spike ?

Where does the word come from ?

A

Ictus - a sudden event (such as a seizure)

Interictal spike - a brief EEG spike occurring between seizure activity

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18
Q

How can an interictal spike be recorded ?

A

Via scalp EEG or depth EEG.

19
Q

What is the cellular marker of an epileptic event ?

How can it be measured ?

A
  • PDS (Paroxysmal Depolarizing Shift) = cellular marker of epileptic event
  • can be recorded on brain slices via field recording or intracellular recording
20
Q

During a PDS, what in the sustained suprathreshold depolarization due to ?
What does this normally cause ?
How does this go wrong during epilepsy ?

A

• 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

21
Q

What are the 3 possible causes of epileptogenesis (shift from normal spikes to PDS) ?

A

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

22
Q

What is the effect of PDS ?

How does it affect surrounding tissue ?

A
  • The PDS causes a burst of action potentials in the the cell
  • This propagates hyperexcitability to surrounding tissue
23
Q

Certain mutations can lead to idiopathic epilepsy.
What receptors can be affected by these ?
Specify if these are gain or loss of fct mutations.

A

Loss of fct mutations for : VGPCs, VGCCs, GABA-ARs

Gain of fct mutations for : VGSCs, nAChR

24
Q

What does the sodium channel mutation in SCN1B lead to ?

A

Generalized epilepsy with febrile seizures plus.

25
Q

What does the potassium channel mutation mutation in KCNQ2, KCNQ3 lead to ?

A

Benign familial neonatal convulsions.

26
Q

What is the goal of anti-epileptic drugs (AEDs) ?
How might they work ?
What is their effect ?

A

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’

27
Q

In theory, how do AEDs decrease excitation ? - increase inhibition ?

A

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

28
Q

What is felbamate ?
How does it work ?
Why is it not used clinically ?

A

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

29
Q

Can postsynaptic AMPAR antagonists be used as AEDs ?

Name a drug if this is relevant.

A
  • too widespread an effect on basal transmission?

• Perampanel = non-competitive AMPAR antagonist –> in phase III clinical trials

30
Q

What is lamotrigine ?

A

And AED that reduces Glu release.

31
Q

Name 6 families of established AEDs (with one drug belonging to each example).

A
  • Hydantoins –> Phenytoin
  • Dibenzapines –> Carbamazepine
  • Succinimides –> Ethosuximide
  • Barbiturates –> Phenobarbitone
  • BDZs –> Diazepam
  • Fatty Acids –> Sodium Valproate
32
Q

Name 3 drugs that decrease the activity of VGSCs.

What property about these drugs is absolutely curcial ?

A

• Phenytoin
• Carbemazepine
• Valproate
All these frugs ensure voltage and ise-dependant inhibition of Na+ channels

33
Q

What does it mean for a VGSC blocker to be “use-dependent” ?

Why is this important ?

A

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.

34
Q

What is ethosuximide ?
How does it work ?
Why is it an AED ?

A

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’).

35
Q

Give an example of a drug that blocks GABA metabolism.

Explain how it achieves this.

A

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).

36
Q

How can GABA action be potentiated ?

Which classes of drugs allow this ?

A

• Increasing postsynaptic efficacy of GABA by allosteric
modulation of GABA-ARs
• BDZs - Diazepam, Clonzepam
• Barbiturates - Phenbarbitone (may also directly increase Cl-flux)

37
Q

Name 7 “newer AEDs”.

A
  • Lamotrigine
  • Gabapentin
  • Topiramate
  • Tiagabine
  • Levetiracetam
  • Vigabatrin
  • Oxcarbazepine
38
Q

When are newer AEDs recommended ?

A

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

39
Q

What is the advantage of voltage- and use-dependent inhibitors of Na+ channels such as lamotrigine or topiramate ?

A

These drugs modify the activity of hyper-excitable cells w/o affecting normal activity.

40
Q

Which drug can inhibit the membrane transport responsible for GABA uptake ?

A

Tiagabine –> selective inhibitor of GAT-I (on neurons and glial cells)

41
Q

How is phenytoin eliminated from the body ?

Explain why its plasma levels must be monitored.

A

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.

42
Q

What dictates the choice of drugs in the treatment of epilepsy ?

A

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.

43
Q

What will be the drug(s) of choice for a :

  • partial seizure
  • generalized tonic-clonic seizure
  • generalized absence seizure
  • statues epilepticus
A

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

44
Q

Which AEDs have potential developmental toxicity ?

A

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

PHAR2005 (24 decks)

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