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BMS 242 - Phys and pharm of cells > CNS pharmacology II > Flashcards

CNS pharmacology II Flashcards

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1
Q

What causes epilepsy?

A

The IMBALANCE between the INHIBITORY and EXCITATORY transmission in the brain

Excitatory = more, leads to:

  • Hyper excitability in the CNS
  • Unprovoked seizures
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2
Q

What is the therapeutic approach to treat epilepsy?

A

INCREASE inhibitory
OR
DECREASE excitatory transmission in the brain

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3
Q

How is epilepsy classified?

What are the groups?

A

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)
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4
Q

Why is there an increase in excitability of the brain in epilepsy?

A

High frequency discharge by a group of neurons

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5
Q

What is the focus of a seizure?

A

SPECIFIC part of the brain where the seizure may begin

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6
Q

What can happen to the activity of the seizure from the focus?

A

Can spread either WITHIN a limited part of the brain (ONE hemisphere)
OR
Over BOTH hemispheres

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7
Q

What are the symptoms of epilepsy?

Examples?

A

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
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8
Q

What are the two types of generalised seizures?

A

1) Grand mall

2) Petite mall

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9
Q

What do EEGs show in grand mall seizures?

What patterns of behaviour do these firing patterns of the neurons cause?

A

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
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10
Q

What are petite mall generalised seizures also known as? Why?

A

ABSENCE SEIZURES

  • Characteristic oscillatory behaviour of the neurons cause the patient to ‘switch off’ for a couple of seconds
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11
Q

What are the characteristic oscillatory behaviour of the neurons in petite mall seizures mediated by?

A

A specific type of voltage gated Ca2+ channel

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12
Q

What can uncontrolled epileptic seizures lead to?

A

Neuronal toxicity and neurodegeneration

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13
Q

What can cause FAMILIAL epilepsy?

A
  • 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
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14
Q

What is the AIM for anti-epileptic drugs?

A

Increase INHIBITORY transmission –> to limit action potential firing

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15
Q

What are 3 targets for anti-epileptic drugs?

A

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

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16
Q

Why target at the level of the metabolism and uptake of GABA?

A

Transmitter stays around for longer

Potentiates GABA transmission

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17
Q

Why target at the level of the enzymes responsible for the breakdown of GABA?

A

Allows levels of GABA to accumulate

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18
Q

What are 4 anti-epileptic drugs that increase GABA transmission?

A

1) BENZODIAZEPINES
2) BARBITURATES
3) UPTAKE INHIBITORS
4) METABOLIC INHIBITORS

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19
Q

How are Benzodiazepines given in the treatment of epilepsy?

A

Intravenously

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20
Q

What are the disadvantages of Benzodiazepines?

A
  • Sedation
  • Tolerance
  • Withdrawal
  • Dependance
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21
Q

What are the disadvantages of Barbiturates?

A
  • Sedation

- Complex pharmacokinetics

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22
Q

What are 2 types of metabolic inhibitors?

A

1) Vigabartin

2) Valproate

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23
Q

What are the disadvantages of Vigabartin?

A

Depression

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24
Q

What are the disadvantages of Valproate?

A
  • High protein binding

- Disturbs the development of the embryo/fetus

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25
What/where is GABA made? What enzyme?
As a SIDE product of the Kreb's cycle From GLUTAMATE By the enzyme GAD
26
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
27
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
28
What causes the break down of GABA?
Action of 2 enzymes: 1) GABA transaminase 2) Succinate-semialdehyde Dehydrogenase
29
What drug targets GABA transaminase? How?
Vigabatrin SUICIDE INHIBITOR - binds to the enzyme with a COVALENT bond, inactivating it completely
30
What drug binds to succinate-semialdehyde Dehydrogenase?
Valproate
31
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
32
What does the HDAC enzyme do?
Regulates chromatin structure and gene transcription
33
As well as increase inhibitory signalling, what is another way to deal with convulsions?
LIMIT excitatory transmission
34
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
35
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
36
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
37
What are the advantages of the Na+ channel blockers used in the treatment of epilepsy?
Not sedative
38
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
39
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)
40
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
41
What are the advantages of Phenytoin?
Non-sedative
42
What are the disadvantages of Phenytoin?
- Ataxia - Headaches - Rashes
43
What is the most commonly used anti-epileptic?
Carbamazepine
44
What are the advantages of Carbamazepine?
Improved side effects and pharmacokinetics (no toxicity)
45
What are the disadvantages of Carbamazepine?
Microsomal enzyme induction - can't be combined with other drugs
46
Which drug is useful for people who can't tolerate Carbamazepine?
Lamotrigine
47
What seizures are Na+ channel blockers NOT useful for?
Absence seizures
48
What treatment is important in the treatment of absence seizures?
T-type channel blockers (Ca2+ channel blockers)
49
Why does blocking T-type channels not cause dramatic problems?
They are SPECIFIC to their function | not required in action potentials or neurotransmitter release
50
What are the drugs that block T-type channels?
1) Ethsuximide | 2) GABApentin
51
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
52
**What are the 4 main causes of epilepsy?
1) Brain trauma 2) Infection 3) Tumours 4) Inherited
53
What are the acquired changes that can happen in epilepsy?
- In response to damage/trauma | - Autoimmune disease can damage the channels
54
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
55
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
56
What is the overall activity in the brain determined by?
The balance between the excitatory and inhibitory input
57
When do seizures occur?
When there is TOO MUCH excitatory activity When there is TOO LITTLE inhibitory activity
58
What mutation in what channel causes epilepsy? (6)
Can have a mutation in ANY of the following channels: - Nav - Kv - Cav - AchR - GABAa - HCN
59
What is the HCN channel?
Hyper-polarisation activated cyclic nucleotide gated channel
60
What does the HCN channel mediate?
Depolarisation - important in the timing of the action potential
61
What does the AchR channel mediate?
Hyperpolarisaion of the postsynaptic membrane
62
What ions move through the HCN channel?
Cations
63
Where is the Nav1.1 channel present?
On the INHIBITORY INTERNEURON
64
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
65
What is the postsynaptic membrane of the inhibitory interneuron?
The dendrites on the excitatory neuron
66
What transmembrane domain is the voltage sensor in Nav and Cav channels?
The 4th transmembrane domain
67
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
68
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
69
What are the MOST severe mutations in the Nav1.1 channel? Why?
Truncation mutations COMPLETE LOSS of function
70
Where are the Nav1.2 channels present?
On the excitatory axon
71
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
72
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
73
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
74
What is the pattern of action potential firing of ANY neuron?
Fires BURTS of action potentials
75
Which channels fine tune how many/how often action potentials occur?
HCN | Kv7.2
76
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
77
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
78
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
79
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
80
Do mutations always mean there is overactivity?
NO - just increases the risk
81
What are 'pain disorders'?
Unpleasant sensory and emotional experience associated with actual or potential tissue damage
82
What is the normal function of pain?
To PROTECT and WARN of damage
83
What can happen in response to pain if Nav1.7 channels are mutated?
1) LOSS of pain | 2) ENHANCEMENT of pain
84
How do mutations in Nav1.7 cause LOSS of pain?
LOSS OF FUNCTION mutation
85
How do mutations in Nav1.7 cause ENHANCEMENT of pain?
GAIN OF FUNCTION mutation
86
Where is the Nav1.7 channel present? What do they mediate?
In the periphery sensory neurons Mediate the depolarisation phase of the action potential
87
Which pain disorder is inherited?
ENHANCEMENT of pain

BMS 242 - Phys and pharm of cells (13 decks)

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