CNS pharmacology II Flashcards
What causes epilepsy?
The IMBALANCE between the INHIBITORY and EXCITATORY transmission in the brain
Excitatory = more, leads to:
- Hyper excitability in the CNS
- Unprovoked seizures
What is the therapeutic approach to treat epilepsy?
INCREASE inhibitory
OR
DECREASE excitatory transmission in the brain
How is epilepsy classified?
What are the groups?
Into different groups, depending on the property of the seizures:
- Partial (spread across ONE hemisphere)
- Generalised (spread across BOTH hemispheres)
- Simple (NO loss of consciousness)
- Complex (Loss of consciousness)
Why is there an increase in excitability of the brain in epilepsy?
High frequency discharge by a group of neurons
What is the focus of a seizure?
SPECIFIC part of the brain where the seizure may begin
What can happen to the activity of the seizure from the focus?
Can spread either WITHIN a limited part of the brain (ONE hemisphere)
OR
Over BOTH hemispheres
What are the symptoms of epilepsy?
Examples?
DEPENDS upon what parts of the brain are affected
Examples:
- In the MOTOR CORTEX: contractions of the motor groups controlled
- In the HYPOTHALAMUS: Autonomic discharge (may lose control of the bladder etc.)
- In the RETICULAR FORMATION: Loss of consciousness
What are the two types of generalised seizures?
1) Grand mall
2) Petite mall
What do EEGs show in grand mall seizures?
What patterns of behaviour do these firing patterns of the neurons cause?
ALL electrodes pick up activity at the same time
Characteristic activity:
- Starts with fast firing (tonic phase)
- -> Patient becomes RIDGID
- Whole motor cortex and other parts of the brain fire in a synchronous way
- -> Whole body RHYTHMIC convulsions
What are petite mall generalised seizures also known as? Why?
ABSENCE SEIZURES
- Characteristic oscillatory behaviour of the neurons cause the patient to ‘switch off’ for a couple of seconds
What are the characteristic oscillatory behaviour of the neurons in petite mall seizures mediated by?
A specific type of voltage gated Ca2+ channel
What can uncontrolled epileptic seizures lead to?
Neuronal toxicity and neurodegeneration
What can cause FAMILIAL epilepsy?
- Mutations in voltage gated Na2+ channels that are involved in the UPSTROKE of action potentials
- Mutations in the K+ channels and in nicotinic receptors in the brain
What is the AIM for anti-epileptic drugs?
Increase INHIBITORY transmission –> to limit action potential firing
What are 3 targets for anti-epileptic drugs?
1) At the level of the GABAa receptor
2) At the level of the metabolism and uptake of GABA (inhibit the uptake of GABA)
3) At the level of the enzymes that are responsible for the breakdown of GABA
Why target at the level of the metabolism and uptake of GABA?
Transmitter stays around for longer
Potentiates GABA transmission
Why target at the level of the enzymes responsible for the breakdown of GABA?
Allows levels of GABA to accumulate
What are 4 anti-epileptic drugs that increase GABA transmission?
1) BENZODIAZEPINES
2) BARBITURATES
3) UPTAKE INHIBITORS
4) METABOLIC INHIBITORS
How are Benzodiazepines given in the treatment of epilepsy?
Intravenously
What are the disadvantages of Benzodiazepines?
- Sedation
- Tolerance
- Withdrawal
- Dependance
What are the disadvantages of Barbiturates?
- Sedation
- Complex pharmacokinetics
What are 2 types of metabolic inhibitors?
1) Vigabartin
2) Valproate
What are the disadvantages of Vigabartin?
Depression
What are the disadvantages of Valproate?
- High protein binding
- Disturbs the development of the embryo/fetus
What/where is GABA made?
What enzyme?
As a SIDE product of the Kreb’s cycle
From GLUTAMATE
By the enzyme GAD
Where is GAD expressed?
What can this information be used to identify?
ONLY in the neurons that use GABA as their neurotransmitter
This information can be used to identify GABAergic neurons
What increases the transcription of GAD?
What does this cause?
Valproic acid (sodium valproate) increases the transcription of GAD
Therefore, increases the production of GABA
What causes the break down of GABA?
Action of 2 enzymes:
1) GABA transaminase
2) Succinate-semialdehyde Dehydrogenase
What drug targets GABA transaminase?
How?
Vigabatrin
SUICIDE INHIBITOR - binds to the enzyme with a COVALENT bond, inactivating it completely
What drug binds to succinate-semialdehyde Dehydrogenase?
Valproate
How can valproate be modified?
What does this drug do?
To sodium valproate
Inhibits the HDAC enzyme –> to promote the transcription of the enzyme (GAD) that synthesises GABA
What does the HDAC enzyme do?
Regulates chromatin structure and gene transcription
As well as increase inhibitory signalling, what is another way to deal with convulsions?
LIMIT excitatory transmission
What are the ways of inhibiting excitatory transmission?
1) At the level of the receptor
2) At the level of the release of glutamate
3) Work a the level of the Na+ receptors
Describe the limiting of excitatory transmission whilst working at the level of the Na+ channels
USE-DEPENDANT Na+ channel inhibitors:
- Blocks channels that have been activated
- Binds to the INACTIVE state of the channel –> prolong inactive state by STABILISATION of this inactive state
- Less channels are available to open
What neurons do use-dependant Na+ channel inhibitors target?
Rapidly firing neurons (most active neurons)
Block excitatory transmission at the focus
To stop seizure from developing and spreading
What are the advantages of the Na+ channel blockers used in the treatment of epilepsy?
Not sedative
What state of the channel do Na+ channel blockers bind to?
Where does this state come from?
Only bind the INACTIVE state
This state ONLY comes from the OPEN state
Why do use-dependant Na+ blockers target the most active neurons?
More neurons enter the ACTIVE state and therefore the INACTIVE state (of which the drug binds to)
What 3 drugs are Na+ channel blockers?
What do these drugs do?
1) Phenytoin
- Treat partial and grand mal epilepsy
2) Carbamazepine
3) Lamotrigine
Control/lower symptoms of a seizure
What are the advantages of Phenytoin?
Non-sedative
What are the disadvantages of Phenytoin?
- Ataxia
- Headaches
- Rashes
What is the most commonly used anti-epileptic?
Carbamazepine
What are the advantages of Carbamazepine?
Improved side effects and pharmacokinetics (no toxicity)
What are the disadvantages of Carbamazepine?
Microsomal enzyme induction - can’t be combined with other drugs
Which drug is useful for people who can’t tolerate Carbamazepine?
Lamotrigine
What seizures are Na+ channel blockers NOT useful for?
Absence seizures
What treatment is important in the treatment of absence seizures?
T-type channel blockers (Ca2+ channel blockers)
Why does blocking T-type channels not cause dramatic problems?
They are SPECIFIC to their function
not required in action potentials or neurotransmitter release
What are the drugs that block T-type channels?
1) Ethsuximide
2) GABApentin
How does GABApentin treat epilepsy?
Controls the trafficking of Ca2+ channels to the plasma membrane
By binding to one of the subunits of the channel
**What are the 4 main causes of epilepsy?
1) Brain trauma
2) Infection
3) Tumours
4) Inherited
What are the acquired changes that can happen in epilepsy?
- In response to damage/trauma
- Autoimmune disease can damage the channels
What is the relationship with epilepsy and episodic ataxia?
Why?
Many people have both
Due to a disruption in the ion channels of the brain
How is the firing of the excitatory neurons normally regulated?
How?
By INHIBITORY INTERNEURONS
By releasing NT onto the excitatory neurons that suppress the activity in the excitatory neurons
What is the overall activity in the brain determined by?
The balance between the excitatory and inhibitory input
When do seizures occur?
When there is TOO MUCH excitatory activity
When there is TOO LITTLE inhibitory activity
What mutation in what channel causes epilepsy? (6)
Can have a mutation in ANY of the following channels:
- Nav
- Kv
- Cav
- AchR
- GABAa
- HCN
What is the HCN channel?
Hyper-polarisation activated cyclic nucleotide gated channel
What does the HCN channel mediate?
Depolarisation - important in the timing of the action potential
What does the AchR channel mediate?
Hyperpolarisaion of the postsynaptic membrane
What ions move through the HCN channel?
Cations
Where is the Nav1.1 channel present?
On the INHIBITORY INTERNEURON
How does the inhibitory interneuron work?
- Releases GABA (inhibitory) - INHIBITING the target neuron by binding to GABA receptors on the postsynaptic membrane
- Leads to HYPERPOLARISATION
What is the postsynaptic membrane of the inhibitory interneuron?
The dendrites on the excitatory neuron
What transmembrane domain is the voltage sensor in Nav and Cav channels?
The 4th transmembrane domain
What mutations in Nav1.1 cause epilepsy?
What are the symptoms?
- MANY different mutations
- Different mutations result in DIFFERENT forms of epilepsy
Symptoms:
- Depend upon WHAT mutation (eg. truncation, missense) and WHERE in the channel
Describe what happens in a +/- Nav1.1 mutation
LOSS of function
- HALF the normal amount of protein made
- Action potential firing is irregular
- Pattern of the release of GABA is different (too LITTLE activity)
- -> LESS suppression of the excitatory neuron –> higher activity in the excitatory
- More at risk of having a seizure
What are the MOST severe mutations in the Nav1.1 channel?
Why?
Truncation mutations
COMPLETE LOSS of function
Where are the Nav1.2 channels present?
On the excitatory axon
How do mutations in the Nav1.2 channels cause epilepsy?
GAIN OF FUNCTION:
- Shift voltage dependance more NEGATIVE
- -> Open at lower potentials
–> Increased excitatory output
Why do mutations in the AchR cause epilepsy?
- Present on the excitatory neuron (downstream of another excitatory neuron)
When mutated –> GOF
–> Increased sensitivity to Ach OR the activation of the receptor leads to a bigger response
- Increase in the overall excitatory output
- -> More prolonged activation
Why do mutations in the GABAaR receptor cause epilepsy?
LOSS OF FUNCTION mutations:
- GABA released from the inhibitory interneuron but there is no activation of the GABAR
–> No contribution to the hyper polarisation of the membrane
–> Membrane of the excitatory neuron is closer to threshold
What is the pattern of action potential firing of ANY neuron?
Fires BURTS of action potentials
Which channels fine tune how many/how often action potentials occur?
HCN
Kv7.2
What happens when excitatory neurons fire an action potential?
What does this cause?
Release Ach onto the next excitatory neuron –> causing it to depolarise!
This causes the spread of electrical activity in epilepsy
What happens when the HCN channels are mutated?
LOSS OF FUNCTION:
- Input into controlling the number/frequency of action potentials is lost
- -> Firing when shouldn’t
Where are the HCN channels present?
How is this different to the Kv7.2 channels?
HCN - on the DENDRITES of the excitatory neurons downstream of the inhibitory interneuron
Kv7.2 - on the AXONS of the excitatory neurons downstream of the inhibitory interneuron
What happens when the Kv7.2 channels are mutated?
LOSS OF FUNCTION:
- Input into controlling the number/frequency of action potentials is lost
- -> Firing when shouldn’t
Do mutations always mean there is overactivity?
NO - just increases the risk
What are ‘pain disorders’?
Unpleasant sensory and emotional experience associated with actual or potential tissue damage
What is the normal function of pain?
To PROTECT and WARN of damage
What can happen in response to pain if Nav1.7 channels are mutated?
1) LOSS of pain
2) ENHANCEMENT of pain
How do mutations in Nav1.7 cause LOSS of pain?
LOSS OF FUNCTION mutation
How do mutations in Nav1.7 cause ENHANCEMENT of pain?
GAIN OF FUNCTION mutation
Where is the Nav1.7 channel present?
What do they mediate?
In the periphery sensory neurons
Mediate the depolarisation phase of the action potential
Which pain disorder is inherited?
ENHANCEMENT of pain
