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

CNS pharmacology I Flashcards

1
Q

What drugs treat anxiety?

A

Anxiolytics

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2
Q

What drugs treat insomnia?

A

Sedatives/hypnotics

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3
Q

Why are similar interventions needed between anxiety and insomnia?

A

They are closely linked - tend to cause each other

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4
Q

What is anxiety a human manifestation of?

How?

A

A FEAR response

  • It is a defensive mechanism
  • Activation of the sympathetic nervous system (fight or flight)
  • May get freezing of behaviour/hiding
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5
Q

How is anxiety classified?

What are the different categories of anxiety?

A

Into categories related to SYMPTOMS and CAUSES

1) Generalised anxiety
2) Panic disorder
3) Phobias
4) PTSD
5) OCD

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6
Q

What is the most difficult anxiety to model? Why?

A

Generalised anxiety

There is no clear reason behind it

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7
Q

What marked symptoms does a panic disorder have?

A

Clear somatic symptoms (eg. sweating, increased heart rate)

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8
Q

What is PTSD associated with?

A

A memory

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9
Q

What is OCD?

A

Ritualistic/repetitive behaviour

Can be seen in animal models

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10
Q

What are 4 treatments of anxiety?

A

1) Benzodiazepines
2) Anti-depressants
3) Buspirone
4) Beta-blockers

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11
Q

What are the advantages of Benzodiazepines?

A
  • Calming effect

- Work quickly

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12
Q

What are the disadvantages of Benzodiazepines?

A

Long-term use:

  • Addiction
  • Tolerance
  • Drowsiness
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13
Q

What are the most common anti-depressants to be prescribed?

A

SSRIs

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14
Q

What are the disadvantages of anti-depressants?

A

Take a long time to work

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15
Q

What is Buspirone?

A

A 5-HT agonist

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16
Q

What are the advantages of Buspirone?

A

Anxiolytic effects WITHOUT the unwanted side effects of Benzodiazepines

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17
Q

What are the disadvantages of Buspirone?

A

Take several weeks to start working

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18
Q

What is propanalol?

What does it block? Why is this advantageous?

A

A beta-blocker

Blocks the PHYSICAL symptoms of the disease, which is enough to get the individual through tough times

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19
Q

How are drugs tested that treat anxiety?

A

As anxiety is a fear response in animals, can subject model organisms to fear and then treat them with drugs - observe effects

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20
Q

What is the amino acid neurotransmitters that are affected in anxiety?

What is this similar to?

What does this mean?

A

GABA neurotransmitter

Similar to epilepsy - same neurotransmitter system

This means that some anti-epileptic drugs can be useful in the treatment of anxiety

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21
Q

What do all the treatments for anxiety do?

A

Interfere with GABA signalling

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22
Q

How many families of GABA receptors are there?

A

2

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23
Q

What type of receptors are the GABAa receptors?

A

Ionotropic receptors (ligand gated)

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24
Q

Where are GABAa receptors found?

A

On the soma and dendrites of neurons in the CNS (postsynaptic)

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25
Q

Where is GABA released from in the brain?

What does it mediate?

A

From interneurons

Mediates INHIBITION

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26
Q

What is the normal function of GABA release from the interneurons?

A

To keep the brain in balance

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27
Q

What ion passes through GABAa receptors?

A

Cl-

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28
Q

What happens when GABAa neurons are open in the postsynaptic membrane?

A

They HYPER POLARISE the neuron - stopping it from reaching threshold

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29
Q

What superfamily does the GABAa receptor belong to?

What else is a member of this family?

A

The NICOTINIC receptor superfamily

Ach nicotinic R is also a member of this family

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30
Q

What is the structure of the GABAa receptor?

A

5 subunits (2 alpha, 2 beta, 1 other)

More than one ligand binding site

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31
Q

How can GABAa receptors vary?

A

Vary in pharmacology, location and function

  • As there are 5 subunits that make up the GABAa receptor
  • But can vary in subunit composition (many different genes that code for the different subunits)
  • Depending on what subunits make up the receptor –> function, location, pharmacology
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32
Q

What is the traditional site where GABA agonist binds to the GABAa receptor?

What happens when this site is bound?

A

The orthosteric site

When bound - the channel opens

33
Q

What are the other drug binding sites on the GABAa receptor?

What happens when drugs bind here?

A

Allosteric sites

When drugs bind here:
- MODIFIES the behaviour of the receptor, only when the orthosteric site is bound

34
Q

What drugs targets the drug binding site on GABAa?

How do they act?

A

1) Diazepam
- Increases the activity of the receptor, underpinning the sedative effects

2) Flumazenil
- Antagonist

3) Beta-Carboline
- INVERSE agonist
- Decreases the responsiveness to GABA

35
Q

What happens if block GABAa in the brain?

Why?

A

Convulsions

Excitatory signals are not balanced

36
Q

Which GABAa receptors are NOT implicated in the treatment of anxiety?

What type of receptors are these?

A

GABAb receptors

Metabotropic receptors (GCPR)

37
Q

What are GABAa receptors targets for?

A
  • Sedatives
  • Anxiolytics
  • Hypnotics
  • Anti-convulsants
  • Some general aneasthetics
38
Q

Where does each drug bind to the GABAa receptor?

A

At DISTINCT sites

39
Q

How many orthosteric sites of the GABAa receptor must be bound to make the channel open?

A

2

40
Q

Which GABAa receptors do Benzodiazepines interact with?

What does this mean?

A

Only CERTAIN subunits (only receptors with alpha 1,2,3,4 or 5 can respond)

Means that in some parts of the brain - there are GABAa receptors that are INSENSITIVE to Benzodiazepine

41
Q

What happens in mice if there is a KO of alpha2?

Why?

A

Mice no longer respond to Benzodiazepine

Due to:
- ONE amino acid change (histadine –> arginine) which removed the Benzodiazepine binding

42
Q

What are the 5 physiological effects to benzodiazepine agonists?

A

1) Sedation/Anxiolytic (less responsive to stressful situations)
2) Hypnosis
3) Anterograde Amnesia (Prevent memory of events whilst under the influence)
4) Anti-convulsant
5) Reduction of muscle tone

43
Q

Describe the action of Benzodiazepines on current through GABAa receptors

A

In presence of Benzodiazepine - current is INCREASED dramatically

When remove Benzodiazepine - current back to normal

44
Q

What is the selectivity of Benzodiazepine?

A

VERY selective, only for GABA receptors

45
Q

How can you get a bigger current from a channel?

A
  • Increase FREQUENCY of channel openings
  • Increase channel OPEN time
  • Decrease channel CLOSE time (different mechanisms to increasing channel open time)
  • Increase channel CONDUCTANCE - more ions through per unit of time
46
Q

How does Benzodiazepine cause a bigger current in the GABA receptor?

A

Make it easier for the the channels to open - increases the FREQUENCY of channel opening times

47
Q

How do Barbiturates act on GABAa channels?

A

Increase the opening TIME

48
Q

What happens if you increase the concentration of Barbiturates high enough?

A

Channels can open, even in the ABSENCE of GABA (ligand)

49
Q

When is the effect of Benzodiazepine only ever seen?

A

In the presence of GABA agonist

50
Q

Where does beta-carboline act?

What are the effects of this drug in comparison to Benzodiazepine?

A

Act at the Benzodiazepine site on the GABAa receptor

Is an INVERSE AGONIST - OPPOSES the effects of Benzodiazepine

51
Q

How does beta-carboline effect the GABAa receptor?

What does this cause?

A
  • DECREASES the frequency of channel opening in the presence of GABA

Causing:

  • A smaller current through the GABAa channel
  • LESS neurons are inhibited
  • May increase learning and memory
52
Q

What can decreasing GABA activity cause?

A

Convulsions

53
Q

What is Flumazenil?

Where does it work?

A

A COMPETITIVE antagonist with Benzodiazepine for the Benzodiazepine binding site on the GABAa receptor

54
Q

What is the action of Flumazenil?

A

No action - only prevents the binding of the agonist

55
Q

What is the only clinical use for Flumazenil?

A

To treat the overdose of Benzodiazepine

56
Q

What are the similarities/differences between some of the Benzodiazepines on the market?

A

Similarities:
- All work in the SAME way

Differences:
- Slightly altered chemically –> have different pharmacokinetics (how quickly distributed/metabolised)

57
Q

What are the 2 most widely used Benzodiazepines?

A

1) Zolpidem

2) Diazepam (Valium)

58
Q

What is Zolpidem useful to treat/not useful to treat and why?

A

Useful to treat INSOMNIA:

  • Rapidly acting sedative
  • Lipophilic - can easily cross the BBB

NOT useful for ANXIETY:
- Short half-life so short duration of action, due to it being rapidly metabolised

59
Q

What are the advantages of using Diazepam (Valium) to treat anxiety?

A

Longer half-life

60
Q

Why does Diazepam have a long half-life?

A
  • When the drug undergoes FIRST PASS metabolism, creates an ACTIVE drug
  • This active drug is another Benzodiazepine agonist –> prolonging the activity
61
Q

What are the disadvantages of using Benzodiazepines?

A

Long duration of action due to the long half-life

Causing many unwanted side effects:

  • Impair motor ability
  • Drowsiness
62
Q

What are 5 the adverse effects of Benzodiazepine agonists?

A

1) Sleepiness, impaired psychomotor function, amnesia
- -> not good for long term use

2) ADDITIVE effects with other CNS depressants (eg. alcohol) –> fatal in overdose
3) TOLERANCE
4) MISUSE
5) PHYSCIAL DEPENDANCE

63
Q

What does the dose-response curve for Benzodiazepines show?

A
  • Sedation at low levels

- As dose increase –> go into hypnosis (where plateau on the graph)

64
Q

Why is there a ‘plateau’ on the dose-response curve of Benzodiazepines?

A

The drug ONLY modifies and increases the action of GABA in parts of the brain where GABA is active

65
Q

What happens in a dose-response curve of Barbiturates?

Why?

A

Anaesthesia, coma, death

In addition to working as ALLOSTEIC agonists, when concentration increases, Barbiturates can have an agonist action against the GABAa receptor

66
Q

What is ‘tolerance’ to a drug?

A

Decreased responsiveness to a drug following continuous exposure

67
Q

What are the 2 difference types of tolerance to a drug?

A

1) At the level of the RECEPTOR
- Receptor CHANGES so they can no longer bind to the drug
2) METABOLIC tolerance
- Body INCREASES the enzyme that breaks down the drug

68
Q

What type of tolerance is common with Barbiturates?

A

Metabolic tolerance

69
Q

Hoe can tolerance be overcome?

A

By increasing dose

70
Q

What is the physical dependance of a drug characterised by?

What is this?

A

Withdrawal syndrome

An exaggerated response of the problem have in the first place

71
Q

What are the symptoms of withdrawal syndrome?

A
  • Increased anxiety
  • Insomnia
  • CNA excitability –> convulsions
72
Q

With what drugs is the withdrawal syndrome more problematic?

A

Drugs with short half-lives

73
Q

What are other anxiolytics and hypnotics that can be used instead of Benzodiazepines?

A

1) Benzodiazepine PARTIAL AGONISTS
2) RECEPTOR SELECTIVE Benzodiazepine agonists
3) NON-BENZODIAZEPINES
4) Beta-adrenoR antagonists (eg. propanolol)
5) Over the counter sleep aids: anti-histamines

74
Q

What are the disadvantages of non-benzodiazepines?

A
  • Doesn’t treat depression

- Takes a while to be affective

75
Q

What are Beta-adrenoR antagonist used for?

A

To block the PHYSICAL SYMPTOMS associated with the activation of the sympathetic nervous system

76
Q

Why are benzodiazepine PARTIAL AGONISTS advantageous?

A

Reduces efficacy –> leads to less tolerance and physical dependance

77
Q

Why are RECEPTOR SELECTIVE Benzodiazepine agonists advantageous?

A

Selective to the parts of the brain involved in anxiety

78
Q

Why are NON-BENZODIAZEPINES advantageous?

A
  • Non-sedative

- Doesn’t have the problems of Benzodiazepines

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

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