Lecture 13 (CNS Pharmacology II - Anti-epileptic drugs)

Question 1

What are the characteristics of epilepsy? (2)

Answer 1

-Unprovoked seizures
-Discharge may be recorded on EEG, helpful in diagnosis

Question 2

What are potential causes of epilepsy? (5)

Answer 2

-Head injury
-Local lesions (age)
-Neoplasms/tumor
-Infection
-Genetic* (ion channels involved in action potential generation, sodium channels, potassium channels, GABAa receptors, nicotinic receptors)

Question 3

What could seizures be triggered by? (4)

Answer 3

-Altered blood glucose or pH
-Stress
-Fatigue
-Flashing lights or noise

Question 4

What causes familial epilepsy?

Answer 4

Gain of function mutations in sodium channels responsible for depolarisation causes hyper-excitability of neurones

(could be loss of function in potassium channels)

Question 5

What do EEGs(electroencephalograms) show for different epileptic seizure types and what are the different types? (3)

Answer 5

Generalised seizure (grand mal) - Synchronised abnormal activity, relaxation and contractions

Generalised seizure (petit mal) - Synchronised abnormal activity, no seizure where you get characteristic oscillating behaviour, usually malfunction in specific ion channel

Partial seizure - Limited to one hemisphere of brain

Question 6

How can you get animal models of epilepsy? (3)

Answer 6

-Genetically modified animals carrying mutations

-Kindling model (repeated low level electrical stimulation of brain regions)

-Chemical model (Penicillin/PTZ injected directly into brain)

Question 7

Which types of drugs targets increase GABA transmission? (3)
(Anti-epileptic drugs)

Answer 7

-GABA A receptor itself (benzodiazepines)
-GABA Uptake inhibitors
-Inhibitors of GABA metabolism

Question 8

Where is GABA synthesised from?

Answer 8

Glutamate which is metabolised as byproduct in Kreb’s cycle

Question 9

What enzyme converts glutamate to GABA?

Answer 9

Glutamic acid decarboxylase

Question 10

What do anti-epileptic drugs aim to do? (3)

Answer 10

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 neurones firing ‘abnormally’

Question 11

What are targets of anti-epileptic drugs?
and why?

Answer 11

-Na channel blockers

-Na channels blockers stop action potentials, decrease in release of excitatory neurotransmitter therefore limit SPREAD

Question 12

What type of blockers do we use in anti-epileptic drugs?

Answer 12

Use-Dependant Blockers

Question 13

What is a problem with anti-epileptic drugs?

Answer 13

Na channels found in all nerves and muscle, not much selectivity so side effects will show

Question 14

What do Use-Dependant sodium channels inhibitors do to inactivated site?
what does this mean? (3)

Answer 14

-These drugs stabilise inactivated state of voltage gated sodium channels

-Slowed down when going back to resting state
-Reduced number of channels available to respond to depolarisation
-Drug works selectively to inactivate hyper-excited neuron channels

(Neurons with most channels in inactivated state are the ones that fire the most APs)

Question 15

What are Na+ channels inhibitors used in epilepsy treatment? (3)

Answer 15

-Phenytoin
-Carbamazepine
-Lamotrigine

Question 16

Where are new drug targets for epilepsy treatment?

Answer 16

Glutamate receptors antagonists

Question 17

What do symptoms of a seizure depends on?

Answer 17

Brain areas affected

Question 18

What symptoms are shown for seizure in: (3)
Motor cortex
Hypothalamus
Reticular formation

Answer 18

Motor cortex - convulsions
Hypothalamus - autonomic discharge
Reticular formation - loss of consciousness

Question 19

What does severity of a seizure depend on? (6)

Answer 19

-Focus
-Spread (whether includes 1 or 2 hemispheres)
-Frequency
-Excitotoxic
-Neuronal death
-Retardation

Question 20

What are the symptoms of a partial seizure? (4)

Answer 20

-Involuntary muscle contraction
-Abnormal sensory experience
-Autonomic discharge
-Effects on mood/behaviour

Question 21

When does a Generalised seizure (petit mal) usually take place?

Answer 21

This type is usually in early childhood, due to malfunction in part of brain that controls oscillatory behaviour, specific ion channel

Question 22

What are the 3 main types of anti-epileptic drugs (increase GABA transmission)? (3)

Answer 22

-Benzodiazepines/Barbiturates
-Uptake inhibitors
-Metbaolic inhibitors

Question 23

What are the 3 functional states of voltage-gated channels? (3)

Answer 23

Resting - the closed state that prevails at the normal resting potential

Activated- the open state favoured by brief depolarisation

Inactivated - the blocked state resulting from a trapdoor-like occlusion of the open channel by a floppy intracellular appendage of the channel protein

Question 24

How are use dependant sodium channel inhibitors used for epilepsy?
What type of seizures are these good for?

Answer 24

-Drug works selectively to inactivate hyper-excited neuron channels
-Prolonging the refractory period and reducing the maximum frequency at which action potentials can be generated

(effective for partial seizures)

Question 25

What do T-type Ca channels and Ca channel trafficking drugs do? (2)

Answer 25

T-type Ca channels
T-channel blocker
(used for generalised absence seizures - petit mal)

Ca channel trafficking
Acts on subunit of calcium channels, restricts their trafficking to the plasma membrane, also used for pain management

Question 26

What are the 4 ways to treat epileptic effects with drugs? (4)

Answer 26

-Increasing GABA transmission
-Use-dependant sodium channel blockers
-T-type Ca channels
-Ca channel trafficking