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CPTP 3 > CPTP 3.3 Neuropharmacology 1 (Antidepressants) > Flashcards

CPTP 3.3 Neuropharmacology 1 (Antidepressants) Flashcards

1
Q

What creates biological vulnerabilities for depression and mood disorders?

A
  • Genetic predisposition

* Early adverse life experiences

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2
Q

Are catecholamines monoamines?

A

Yes

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3
Q

list the catecholamines

A
  • NA
    • Serotonin
    • Dopamine
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4
Q

Outline briefly the monoamine hypothesis?

A

Depression is due to a deficit in central monoamine neurotransmission.

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5
Q

What evidence is there against monoamine theory?

A
  • Cocaine inhibits NA uptake, but isn’s an antidepressant

* Lowered monoamines aren’t seen in patients with depression

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6
Q

Outline the biochemical pathway for the synthesis of 5-HT

A

Tryptophan –TPH–> 5-HTP
5-HTP –AADC–> 5-HT

TPH = tyrptophan hydroxylase
AADC = 5-hydroxytryptophan decarboxylase
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7
Q

What occurs to 5-HT after synthesis?

A

Either stored into vesicles or broken down by MAO into 5-HIAA and extruded

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8
Q

What are the most important postsynaptic 5-HT receptors?

A
  • 5-HT 1A
    • 5-HT 1B
    • 5-HT 2A
    • 5-HT 2C
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9
Q

What is the 5-HT autoreceptor?

A

5-HT 1A

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10
Q

How is serotonin terminated?

A

SERT in the presynaptic membrane pumps 5-HT back into the presynaptic neurone.

It can then either be transported back into vesicles or broken down by MAO

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11
Q

What two pharmacological targets are there for antidepressants?

A

The termination step:
• MAO
• SERT

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12
Q

Which antidepressants block 5-HT reuptake?

A
  • Tricyclic antidepressants
    • SSRIs
    • SNRIs (serotonin & noradrenaline)
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13
Q

Which antidepressants block NA reuptake?

A
  • SNRIs (serotonin & noradrenaline)

* NARIs

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14
Q

What effect do reuptake inhibitors have?

A

They prolong the effects of the neurotransmitter

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15
Q

What are the clinical limitations of TCAs?

A
  • Delayed onset of 2 weeks before effective
    • M1 antagonistic effects
    • H1 antagonistic effects
    • a1-adrenoreceptor antagonistic effects
    • Cardiotoxic in overdose
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16
Q

What do TCA M1 antagonistic side effects include?

A
  • dry mouth
    • blurred vision
    • constipation
    • urinary retention
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17
Q

What do TCA H1 antagonistic side effects include?

A
  • Sedation

* Weight gain

18
Q

What do TCA a1 antagonistic side effects include?

A

Postural hypotension

19
Q

What do the clinical limitations of TCAs result in?

A

Feeling worse before you feel better because the side effects are immediate but the therapeutic effects are delayed

This results in poor compliance

20
Q

What are the benefits of TCAs

A
  • Can be used for severe or resistant (other drugs aren’t working) depression
    • They are cheap
21
Q

In what groups are TCAs not used?

A
  • Elderly
    • Young
    • Cardiac patients
    • Suicidal patients (overdose)
    • Drivers (sedation)
22
Q

Why are TCAs not used in cardiac patients?

A

They increase the chance of conduction abnormalities.

23
Q

What are the ‘second generation’ antidepressant classes? What is special about these?

A

• SSRIs
• SNRIs
• NARI
Selective for 5-HT or NA transporters and do not have affinity for postsynaptic receptors so there are fewer side-effects

24
Q

How do SSRI and SNRI efficacies compare to those of TCAs?

A

The same (but far fewer side-effects) “Clean drugs”, high selectivity

25
Q

What do the isoforms of MAO do?

A
  • MAO A breaks down 5-HT and NA

* MAO B breaks down Dopamine

26
Q

What does older MAOIs do? Name the one in the formulary. What are the downsides to these?

A

Blocks both isoforms of MAO irreversibly.

Phenelzine

  • Stimulant effects
  • Dangerous in overdose
27
Q

What do new MAOIs do?

A

Reversible inhibitors of monoamine oxidase A (RIMA)

  • Selective for MAO A
  • Reversible
  • Dont have the downsides of older MAOIs
28
Q

What is the main side effect of MAOIs?

A

The cheese effect:
• MAO in gut and periphery usually breaks down dietary amines
• If MAOIs are used in a diet high in amines, this leads to a increased amine absorption
• Noradrenaline is displaced by these amines causing a hypertensive crisis

29
Q

What is serotonin syndrome?

A

Result of drug-drug interaction between MAOIs and SSRIs
• Hyperthermia
• Confusion
• Hypertensive crisis

30
Q

When does serotonin syndrome most commonly occur?

A

When switching between MAOIs and SSRIs due to the half lives of some of these drugs being high

31
Q

Which SSRI has a long half life?

A

Fluoxetine

32
Q

How long do you need to wait when making the following drug switches:

1) MAOI –> Fluoxetine
2) Fluoxetine -> MAOI

A

1) 2 weeks

2) 5 weeks

33
Q

What are atypical antidepressants?

A

NEWER antidepressants with an affinity for a range of monoamine transporters and receptors (NaSSA)

34
Q

Name the atypical antidepressant in the student formulary

A

Mirtazepine

35
Q

How can 5-HT synthesis be increased? How clinically effective is this?

A

Increasing precursor availability by giving a tryptophan load

Not clinically effective on its own but increases therapeutic response of other antidepressant treatments.

36
Q

How can 5-HT release be increased?

What is the limitation of this?

A

By using a releasing agent such as MDMA

Causes long-term neurotoxicity

37
Q

What causes the delayed onset of action of antidepressants?

A

Neurotrophic hypothesis:
• SSRIs cause acute increase in 5-HT, but the therapeutic effect is a result of the synaptic remodelling caused by 5-HT’s trophism role
• Synaptic remodelling takes time

Autoreceptor hypothesis:
• The acute increase in 5-HT activates autoreceptors, restraining the ability of SSRIs to maintain synaptic 5-HT
• Therapeutic effects arise when these autoreceptors are desensitised

38
Q

Where do serotonergic and noradernergic neurones begin and end?

A 
Serotonin:
  •  Starts at raphe nuclei
Noradrenaline:
  •  Lateral tegmentum
  •  Locus ceruleus

BOTH PROJECT THROUGHOUT THE FOREBRAIN

39
Q

Where is 5-HTT (5-HT transporter) most densely expressed? What else is densely expressed here and what is the significance of this?

A

Dorsal raphe nucleus

5-HT 1A receptors

This is where autoreception and thus negative feedback mostly occurs

40
Q

What protein do SSRIs inhibit?

A

5-HTT transporters in dorsal raphe nucleus

41
Q

What are the acute effects of SSRI action?

A
  • 5-HTT transporters blocked
    • DRN 5-HT levels rise
    • 5-HT 1A autoreceptors stimulated
    • Firing is inhibited
    • Terminal release is inhibited

This results in acute side effects before the 5-HT 1A receptors are desensitised

42
Q

What are the side effects of SSRIs?

A
  • Nausea
    • Impotence
    • Weight gain

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