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

CNS pharmacology II Flashcards

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
Q

What/where is GABA made?

What enzyme?

A

As a SIDE product of the Kreb’s cycle

From GLUTAMATE
By the enzyme GAD

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26
Q

Where is GAD expressed?

What can this information be used to identify?

A

ONLY in the neurons that use GABA as their neurotransmitter

This information can be used to identify GABAergic neurons

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27
Q

What increases the transcription of GAD?

What does this cause?

A

Valproic acid (sodium valproate) increases the transcription of GAD

Therefore, increases the production of GABA

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28
Q

What causes the break down of GABA?

A

Action of 2 enzymes:
1) GABA transaminase

2) Succinate-semialdehyde Dehydrogenase

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29
Q

What drug targets GABA transaminase?

How?

A

Vigabatrin

SUICIDE INHIBITOR - binds to the enzyme with a COVALENT bond, inactivating it completely

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30
Q

What drug binds to succinate-semialdehyde Dehydrogenase?

A

Valproate

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31
Q

How can valproate be modified?

What does this drug do?

A

To sodium valproate

Inhibits the HDAC enzyme –> to promote the transcription of the enzyme (GAD) that synthesises GABA

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32
Q

What does the HDAC enzyme do?

A

Regulates chromatin structure and gene transcription

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33
Q

As well as increase inhibitory signalling, what is another way to deal with convulsions?

A

LIMIT excitatory transmission

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34
Q

What are the ways of inhibiting excitatory transmission?

A

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

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35
Q

Describe the limiting of excitatory transmission whilst working at the level of the Na+ channels

A

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
Q

What neurons do use-dependant Na+ channel inhibitors target?

A

Rapidly firing neurons (most active neurons)

Block excitatory transmission at the focus

To stop seizure from developing and spreading

37
Q

What are the advantages of the Na+ channel blockers used in the treatment of epilepsy?

A

Not sedative

38
Q

What state of the channel do Na+ channel blockers bind to?

Where does this state come from?

A

Only bind the INACTIVE state

This state ONLY comes from the OPEN state

39
Q

Why do use-dependant Na+ blockers target the most active neurons?

A

More neurons enter the ACTIVE state and therefore the INACTIVE state (of which the drug binds to)

40
Q

What 3 drugs are Na+ channel blockers?

What do these drugs do?

A

1) Phenytoin
- Treat partial and grand mal epilepsy

2) Carbamazepine
3) Lamotrigine

Control/lower symptoms of a seizure

41
Q

What are the advantages of Phenytoin?

A

Non-sedative

42
Q

What are the disadvantages of Phenytoin?

A
  • Ataxia
  • Headaches
  • Rashes
43
Q

What is the most commonly used anti-epileptic?

A

Carbamazepine

44
Q

What are the advantages of Carbamazepine?

A

Improved side effects and pharmacokinetics (no toxicity)

45
Q

What are the disadvantages of Carbamazepine?

A

Microsomal enzyme induction - can’t be combined with other drugs

46
Q

Which drug is useful for people who can’t tolerate Carbamazepine?

A

Lamotrigine

47
Q

What seizures are Na+ channel blockers NOT useful for?

A

Absence seizures

48
Q

What treatment is important in the treatment of absence seizures?

A

T-type channel blockers (Ca2+ channel blockers)

49
Q

Why does blocking T-type channels not cause dramatic problems?

A

They are SPECIFIC to their function

not required in action potentials or neurotransmitter release

50
Q

What are the drugs that block T-type channels?

A

1) Ethsuximide

2) GABApentin

51
Q

How does GABApentin treat epilepsy?

A

Controls the trafficking of Ca2+ channels to the plasma membrane

By binding to one of the subunits of the channel

52
Q

**What are the 4 main causes of epilepsy?

A

1) Brain trauma
2) Infection
3) Tumours
4) Inherited

53
Q

What are the acquired changes that can happen in epilepsy?

A
  • In response to damage/trauma

- Autoimmune disease can damage the channels

54
Q

What is the relationship with epilepsy and episodic ataxia?

Why?

A

Many people have both

Due to a disruption in the ion channels of the brain

55
Q

How is the firing of the excitatory neurons normally regulated?

How?

A

By INHIBITORY INTERNEURONS

By releasing NT onto the excitatory neurons that suppress the activity in the excitatory neurons

56
Q

What is the overall activity in the brain determined by?

A

The balance between the excitatory and inhibitory input

57
Q

When do seizures occur?

A

When there is TOO MUCH excitatory activity

When there is TOO LITTLE inhibitory activity

58
Q

What mutation in what channel causes epilepsy? (6)

A

Can have a mutation in ANY of the following channels:

  • Nav
  • Kv
  • Cav
  • AchR
  • GABAa
  • HCN
59
Q

What is the HCN channel?

A

Hyper-polarisation activated cyclic nucleotide gated channel

60
Q

What does the HCN channel mediate?

A

Depolarisation - important in the timing of the action potential

61
Q

What does the AchR channel mediate?

A

Hyperpolarisaion of the postsynaptic membrane

62
Q

What ions move through the HCN channel?

A

Cations

63
Q

Where is the Nav1.1 channel present?

A

On the INHIBITORY INTERNEURON

64
Q

How does the inhibitory interneuron work?

A
  • Releases GABA (inhibitory) - INHIBITING the target neuron by binding to GABA receptors on the postsynaptic membrane
  • Leads to HYPERPOLARISATION
65
Q

What is the postsynaptic membrane of the inhibitory interneuron?

A

The dendrites on the excitatory neuron

66
Q

What transmembrane domain is the voltage sensor in Nav and Cav channels?

A

The 4th transmembrane domain

67
Q

What mutations in Nav1.1 cause epilepsy?

What are the symptoms?

A
  • 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
Q

Describe what happens in a +/- Nav1.1 mutation

A

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
Q

What are the MOST severe mutations in the Nav1.1 channel?

Why?

A

Truncation mutations

COMPLETE LOSS of function

70
Q

Where are the Nav1.2 channels present?

A

On the excitatory axon

71
Q

How do mutations in the Nav1.2 channels cause epilepsy?

A

GAIN OF FUNCTION:

  • Shift voltage dependance more NEGATIVE
  • -> Open at lower potentials

–> Increased excitatory output

72
Q

Why do mutations in the AchR cause epilepsy?

A
  • 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
Q

Why do mutations in the GABAaR receptor cause epilepsy?

A

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
Q

What is the pattern of action potential firing of ANY neuron?

A

Fires BURTS of action potentials

75
Q

Which channels fine tune how many/how often action potentials occur?

A

HCN

Kv7.2

76
Q

What happens when excitatory neurons fire an action potential?

What does this cause?

A

Release Ach onto the next excitatory neuron –> causing it to depolarise!

This causes the spread of electrical activity in epilepsy

77
Q

What happens when the HCN channels are mutated?

A

LOSS OF FUNCTION:

  • Input into controlling the number/frequency of action potentials is lost
  • -> Firing when shouldn’t
78
Q

Where are the HCN channels present?

How is this different to the Kv7.2 channels?

A

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
Q

What happens when the Kv7.2 channels are mutated?

A

LOSS OF FUNCTION:

  • Input into controlling the number/frequency of action potentials is lost
  • -> Firing when shouldn’t
80
Q

Do mutations always mean there is overactivity?

A

NO - just increases the risk

81
Q

What are ‘pain disorders’?

A

Unpleasant sensory and emotional experience associated with actual or potential tissue damage

82
Q

What is the normal function of pain?

A

To PROTECT and WARN of damage

83
Q

What can happen in response to pain if Nav1.7 channels are mutated?

A

1) LOSS of pain

2) ENHANCEMENT of pain

84
Q

How do mutations in Nav1.7 cause LOSS of pain?

A

LOSS OF FUNCTION mutation

85
Q

How do mutations in Nav1.7 cause ENHANCEMENT of pain?

A

GAIN OF FUNCTION mutation

86
Q

Where is the Nav1.7 channel present?

What do they mediate?

A

In the periphery sensory neurons

Mediate the depolarisation phase of the action potential

87
Q

Which pain disorder is inherited?

A

ENHANCEMENT of pain

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

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