Lecture 13 (CNS Pharmacology II - Anti-epileptic drugs) Flashcards
What are the characteristics of epilepsy? (2)
-Unprovoked seizures
-Discharge may be recorded on EEG, helpful in diagnosis
What are potential causes of epilepsy? (5)
-Head injury
-Local lesions (age)
-Neoplasms/tumor
-Infection
-Genetic* (ion channels involved in action potential generation, sodium channels, potassium channels, GABAa receptors, nicotinic receptors)
What could seizures be triggered by? (4)
-Altered blood glucose or pH
-Stress
-Fatigue
-Flashing lights or noise
What causes familial epilepsy?
Gain of function mutations in sodium channels responsible for depolarisation causes hyper-excitability of neurones
(could be loss of function in potassium channels)
What do EEGs(electroencephalograms) show for different epileptic seizure types and what are the different types? (3)
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
How can you get animal models of epilepsy? (3)
-Genetically modified animals carrying mutations
-Kindling model (repeated low level electrical stimulation of brain regions)
-Chemical model (Penicillin/PTZ injected directly into brain)
Which types of drugs targets increase GABA transmission? (3)
(Anti-epileptic drugs)
-GABA A receptor itself (benzodiazepines)
-GABA Uptake inhibitors
-Inhibitors of GABA metabolism
Where is GABA synthesised from?
Glutamate which is metabolised as byproduct in Kreb’s cycle
What enzyme converts glutamate to GABA?
Glutamic acid decarboxylase
What do anti-epileptic drugs aim to do? (3)
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’
What are targets of anti-epileptic drugs?
and why?
-Na channel blockers
-Na channels blockers stop action potentials, decrease in release of excitatory neurotransmitter therefore limit SPREAD
What type of blockers do we use in anti-epileptic drugs?
Use-Dependant Blockers
What is a problem with anti-epileptic drugs?
Na channels found in all nerves and muscle, not much selectivity so side effects will show
What do Use-Dependant sodium channels inhibitors do to inactivated site?
what does this mean? (3)
-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)
What are Na+ channels inhibitors used in epilepsy treatment? (3)
-Phenytoin
-Carbamazepine
-Lamotrigine
Where are new drug targets for epilepsy treatment?
Glutamate receptors antagonists
What do symptoms of a seizure depends on?
Brain areas affected
What symptoms are shown for seizure in: (3)
Motor cortex
Hypothalamus
Reticular formation
Motor cortex - convulsions
Hypothalamus - autonomic discharge
Reticular formation - loss of consciousness
What does severity of a seizure depend on? (6)
-Focus
-Spread (whether includes 1 or 2 hemispheres)
-Frequency
-Excitotoxic
-Neuronal death
-Retardation
What are the symptoms of a partial seizure? (4)
-Involuntary muscle contraction
-Abnormal sensory experience
-Autonomic discharge
-Effects on mood/behaviour
When does a Generalised seizure (petit mal) usually take place?
This type is usually in early childhood, due to malfunction in part of brain that controls oscillatory behaviour, specific ion channel
What are the 3 main types of anti-epileptic drugs (increase GABA transmission)? (3)
-Benzodiazepines/Barbiturates
-Uptake inhibitors
-Metbaolic inhibitors
What are the 3 functional states of voltage-gated channels? (3)
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
How are use dependant sodium channel inhibitors used for epilepsy?
What type of seizures are these good for?
-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)
What do T-type Ca channels and Ca channel trafficking drugs do? (2)
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
What are the 4 ways to treat epileptic effects with drugs? (4)
-Increasing GABA transmission
-Use-dependant sodium channel blockers
-T-type Ca channels
-Ca channel trafficking
