Lecture 11 - Drug action in the central nervous system - epilepsy (antiepileptics/anticonvulsants)

Question 1

What causes convulsions?

Answer 1

An imbalance between excitatory and inhibitory neurotrasmission, involving the neurotramsitters glutamate & GABA.

Note the abnormal hyperactivity of groups of neurons are also involved in other conditions including pain, anxiety and bipolar disorder. Some anticonvulsants have also found use in treatment of these conditions.

Question 2

What is epilepsy?

Answer 2

• Unprovoked seizures
• High frequency discharge by a group of neurons
• Focus + spread
• Partial or generalised
• Diagnosis with EEG

Disorder including hyperexcitability of the CNS, treated with anticonvulsants

• 1/2000

Question 3

What are causes of epilepsy?

Answer 3

Head injury, local lesions (age), neoplasms/tumour, infection, genetic (ion channels involved in action potential generation - sodium channels, potassium channels, GABAa receptors, nicotinic receptors)

Question 4

Describe the characteristics of epilepsy?

Answer 4

Discharge may be recorded on EEG, helpful in diagnosis

Question 5

What are the symptoms of epilepsy?

Answer 5

Depends on brain areas affected:
- motor cortex = convulsions
- hypothalamus = autonomic discharge
- reticular formation = loss of consciousness

Question 6

What are seizures precipitated (triggered) by?

Answer 6

• altered blood glucose or pH
• stress
• fatigue
• flashing lights or noise

Question 7

What does severity & treatment depend on?

Answer 7

Depends on focus, spread whether includes 1 or 2 hemispheres, frequency, excitotoxic, neuronal death, retardation

Question 8

What do EEGs show with epileptic seizures?

Answer 8

EEGs show abnormal neuronal firing pattern associated with epileptic seizures

Question 9

Describe features of a partial seizure

Answer 9

• discharge begins locally & often remains localised
• symptoms - involuntary muscle contraction, abnormal sensory experience, autonomic discharge, or effects on mood/behaviour (referred to as psychomotor epilepsy)
• usually confined to one hemisphere
• often attributed to local cerebral lesion, incidence increases with age

Question 10

What is autonomic discharge?

Answer 10

Autonomic discharge refers to the activation or outflow of electrical impulses from the autonomic nervous system (ANS), which controls involuntary body functions like heart rate, digestion, respiratory rate etc.

Question 11

Described features of a generalised seizure

Answer 11

• whole brain involved
• immediate loss of consciousness common (seizure spreads to reticular formation)
• include tonic-clonic and absence seizures (common in children) - treatment for the latter involves different types of drugs, as calcium channels appear to be involved.
• can be simple (consciousness is NOT lost) or complex (consciousness IS lost)
• Status epilepticus - when seizure doesn’t stop, medical emergency

Question 12

What is the aim of anti-epileptic drugs?

Answer 12

To inhibit abnormal neuronal discharge - doesn’t cure underlying cause. If not well controlled get excitotoxicity, neuronal death. Ultimately, epilepsy and seizures caused by a balance between excitatory and inhibitory transmission.

Question 13

What is the strategy of anti-epileptic drugs?

Answer 13

Either decrease excitatory neurotransmission or increase inhibitory neurotransmission

Question 14

What can cause familial epilepsy?

Answer 14

Mutations in voltage-gated sodium channels
- gain of function mutations in sodium channels for responsible for depolarisation causes hyperexcitability of neurons
- knowledge of mutations causing epilepsy can be exploited to generate animal models of the condition to test anti-convulsants

Question 15

What are animal models of epilepsy?

Answer 15

‘Chemical models’ - Penicillin crystals, PTZ, Kainate
‘Kindling model’ - repeated low level electrical stimulation

Genetically modified animals carrying mutations

Animal models of epilepsy (mammals, zebrafish) include genetic, chemical and electrical induced convulsants.

Question 16

What can chemicals such as penicillin or pentylene-tetrazol (PTZ) be used for?

Answer 16

Penicillin (inhibits GABAa receptors) or pentylene-tetrazol (PTZ), can be used to trigger acute seizures.

Question 17

What does repeated kainic acid injections lead to?

Answer 17

Kainic acid injections into specific regions, to cause excitotoxicity and local damage of inhibitory neurons results in spontaneous seizures occurring after a few weeks delay - shows that adaptive changes in neural networks contribute to seizure spread from focus.

Question 18

What is the kindling model?

Answer 18

Repeated low level electrical stimulation of brain regions (kindling model) to cause localised hypersensitivity and adaptive changes in network, also leads to production of an animal that shows spontaneous seizures.

Question 19

How do you counterbalance hyperexcitability of CNS?

Answer 19

By increasing inhibitory neurotransmission - this is done by increasing GABA mediated neurotransmission

Question 20

What 3 drugs increase GABA neurotransmission?

Answer 20

• GABAa receptor itself, increasing its activity
• GABA uptake inhibitors
• Inhibitors of GABA metabolism

Last 2 will affect all GABA neurotransmission (less selective), while drugs acting at specific receptor may be somewhat more ‘selective’

Question 21

Describe types of antiepileptic drugs involved in increasing GABA transmission

Answer 21

1. Benzodiazepines - e.g. diazepam (used for intravenously for status epilepticus)
   problems - sedation, tolerance, withdrawal
2. Barbiturates - e.g. phenobarbitone
   problems - low therapeutic index, sedation, complex and pharmacokinetics

Question 22

What are 3 ways of increasing GABA transmission?

Answer 22

1. Benzodiazepines & Barbiturates
2. Uptake inhibitors
   3, Metabolic inhibitors

Question 23

What is an example of an uptake inhibitors?

Answer 23

Tiagabine

Question 24

What are examples of metabolic inhibitors?

Answer 24

Vigabatrin - problems: depression
Valproate - problems: high protein binding, occasionally hepatotoxic and teratogenic (can cause birth defects if taken when pregnant).

Question 25

What is Valproic acid?

Answer 25

an anti-convulsant that is unusual, as it has broad activity against both generalised and partial seizures. It also acts as a mood stabilizer in bipolar & effective in migraine treatment. It has few side-effects, and severe reactions e.g. liver toxicity are rare.

However, it is still controversial - many studies focused on its ability to dampen neuronal hyperexcitability by potentiation of inhibitory neurotransmission.

It is thought to affect GABA metabolism, since valproic acid resembles GABA chemically.

Question 26

Describe features of Valproate

Answer 26

It increased brain levels of GABA, initially suspected to be through inhibition of GABA aminotransferase. However, other GABA metabolizing enzymes have been suggested as more plausible targets in the GABAergic system.

More recent studies have shown new activities for valproate including effects on voltage-gated sodium channels

Question 27

What are the effects of sodium valproate?

Answer 27

The chronic antiepileptic effects of valproate may be due in part to HDAC (histone deacetylases) - mediated regulation of GABA synthetic enzyme, glutamate decarboxylase - increased expression, increased synthesis of GABA.

Question 28

What do HDACs (histone deacetylases) do?

Answer 28

remove histone acetyl group, while valproic acid (VA), other HDAC inhibitors, inhibit this process, allowing histone acetylation and gene activation.

Question 29

What are the aims of antiepileptic drugs?

Answer 29

• decrease excitatory neurotransmission (mediated primarily by glutamate) in brain areas involved.
• stop high frequency discharge from occurring in the first place or limit its spread
• limit action potential generation/propagation in neurons firing ‘abnormally’

Question 30

What are the targets of antiepileptic drugs?

Answer 30

• Na channels blockers stop action potentials
• decrease in release of excitatory neurotransmitter therefore limit SPREAD
• IMOORTANT THAY THESE ONLY ACT ON NEURONS BEHAVING ABNORMALLY - i.e. discharging at high frequency - want other nervous system functions to continue - therefore need to use USE-DEPENDENT blockers

Question 31

What are use-dependent blockers?

Answer 31

Use-dependent blockers are drugs that become more effective as the neuron or channel they are targeting is actively firing or being used. In other words, these blockers are more likely to affect neurons or ion channels that are in an active, excited state, and have less effect on resting or inactive neurons.

Question 32

What are problems for antiepileptic drugs?

Answer 32

Na+ channels found in all nerves and muscle, drugs currently available don’t show much selectivity from the channel point of view and therefore do have side effects

Question 33

What do use-dependent sodium channel inhibitors do?

Answer 33

Stabilize the inactivated state

Question 34

What effect do antiepileptics have on the refractory period?

Answer 34

Antiepileptics prolong the refractory period in neurons and therefore reduce the maximum frequency at which action potentials can be generated. This type of block is called use-dependent, because the binding of such drugs increases as a function of the rate of action potential discharge, which governs the rate of action potential discharge, which governs the rate at which inactivated and therefore drug-sensitive-channels are generated.

Question 35

Describe how Na+ channel inhibitors are used in the trearment of epilepsy

Answer 35

• stabilize inactivated state of the chemical, advantage is not sedative

Phenytoin - (problems) - complex pharmacokinetics, vertigo (dizziness), ataxia (lack of muscle coordination), headaches, rashes etc.

Carbamazepine - most widely used anti-epileptic - (problems) - microsomal enzyme induction (increased production of enzymes e.g. P450 enzymes in liver involved in drug metabolism), shouldn’t be combined with other drugs

Lamotrigine - (problems) - nausea, dizziness, ataxia, rashes

Question 36

Describe how antiepileptic drugs may be Ca2+ channel regulators

Answer 36

T-type Ca+ channel inhibitors used for absence seizures - Ethosuximide

Ca channel trafficking
- GANApentin & pregabalin (bind to a2theta subunit of Calcium channels to reduce ‘trafficking of channel’ to plasma membrane

Question 37

What are new drug targets for the treatment of epilepsy?

Answer 37

Levetiracetam - may act at level of synaptic transmission, limit glutamate transmission through presynaptic mechanism