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Pharmacology > Antidepressants (L15) > Flashcards

Antidepressants (L15) Flashcards

1
Q

symptoms of depression

A
  • low mood
  • guilt
  • hopelessness
  • anhedonia
  • suicidality
  • disturbed sleep
  • altered appetite
  • poor concentration
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2
Q

what is anhedonia?

A

inability to experience pleasure

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3
Q

facts of depression

A
  • 10% prevalence
  • 17% lifetime risk
  • long episodes
  • recurrent course
  • high economic cost
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4
Q

pathology of depression

A

the pathology of depression is unknown

the pharmacology of effective anti-depressant drugs suggests 5-HT and/or NA dysfunction in the brain

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5
Q

major classical transmitters in the CNS

A

noradrenaline (NA)

5-hydroxytryptamine (5-HT)

dopamine (DA)

acetylcholine (ACh)

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6
Q

noradrenergic (NA) pathways in the brain

A

locus coeruleus contains NAergic cell bodies
• projections to the hypothalamus and midbrain
• projections to the hippocampus and cortex

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7
Q

serotonergic (5-HT) pathways in the brain

A

dorsal and median raphe nuclei contain serotonergic cell bodies
• projections to the hypothalamus, hippocampus and cortex

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8
Q

what are the elements of neurotransmission?

A
  • synthesis
  • storage
  • release
  • interaction with target
  • termination
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9
Q

NA/5-HT neurotransmission

A

neurotransmitter parcelled into vesicles, if not broken down by intracellular MAO

neurotransmitters synthesised from AAs

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10
Q

noradrenaline (NA) synthesis

A 
TYROSINE 
    • tyrosine hydroxylase 
L-DOPA 
    • DOPA decarboxylase 
DOPMAINE 
    • dopamine-beta-hydroxylase
NORADRENALINE
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11
Q

rate limiting step in NA synthesis

A

tyrosine hydroxylase

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12
Q

5-HT synthesis

A 
TRYPTOPHAN 
    • tryptophan hydroxylase 
5-HTP
    • 5-HTP decarboxylase 
5-HT
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13
Q

rate limiting step in 5-HT synthesis

A

tryptophan hydroxylase

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14
Q

what are the 2 types of MAO and what neurotransmitters do they metabolise?

A

MAO-A and MAO-B

NA and 5-HT metabolised by both MAO-A and B

DA preferentially metabolised by MAO-B

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15
Q

what does MAO do to the neurotransmitters?

A

they remove the amine group so it can no longer do its job as a neurotransmitter

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16
Q

NA and 5-HT receptors

A

interaction with the target

different kind of receptors in different places

receptors can be on the presynaptic and postsynaptic membranes

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17
Q

what are the different kinds of NA receptors?

A 
alpha and beta 
GPCRs 
• alpha-1
• alpha-2
• beta-1,2,3
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18
Q

alpha-1 NA receptors

A

excitatory
• stimulate PI cycle
• increase DAG
• increase [Ca+]

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19
Q

alpha-2 NA receptors

A

inhibitory
• inhibit adenylate cyclase
• decreases cAMP
• opens K+ channels

20
Q

beta-1,2,3 NA receptors

A

excitatory
• stimulate adenylate cyclase
• increases cAMP

21
Q

what are the different kinds of 5-HT receptors?

A

5-HT
• 1A, 1B, 1D, 1E, 1F, 2A, 2C, 3, 4, 5, 6, 7

GPCR OR ligand gated ion channels

22
Q

GPCR 5-HT receptors

A

5-HT: 1(A-F)
• inhibit adenylate cyclase
• decrease cAMP

5-HT: 2(A-C)
• stimulate PI cycle
• increase DAG
• increase [Ca+]

23
Q

ligand gated ion channel 5-HT receptors

A

5-HT 3

24
Q

what are auto receptors?

A

they are on the presynaptic membrane and are part of a negative feedback loop

they inhibit transmitter release

25
Q

NA terminal autoreceptors

A

alpha-2

26
Q

5-HT terminal autoreceptors

A

5-HT 1B

27
Q

pharmacology of depression

A

1950s
• iproniazid and imipramine found to elevate mood

iproniazid found to inhibit MAO

imipramine found to inhibit NA/5-HT reuptake

28
Q

monoamine theory of depression

A

relative decrease in NA and/or 5-HT neurotransmission underlies the symptoms of depression

29
Q

pharmacotherapeutic aim of anti-depressants

A

to increase NA and/or 5-HT neurotransmission

30
Q

problems with making anti-depressants

A

nature of dysfunction unknown

brain regions affected unknown

31
Q

major classes of antidepressants

A

MAO inhibitors
• reversible, irreversible
• selective, non-selective

MA reuptake inhibitors
• selective, non-selective

32
Q

MAOIs

A

inhibit MAO

inhibit intracellular metabolism of 5-HT

increase vascular 5-HT content

increases 5-HT release

33
Q

examples of MAOI antidepressants

A

irreversible MAO-A/B inhibitors
• tranylcypromine

irreversible MAO-A inhibitors
• clorgyline

reversible inhibitor of MAO-A (RIMA)
• moclobemide

34
Q

side effects and interactions of MAOIs

A

increase DA transmission - stimulant

increase actions of sympathomimetic amines (cheese reaction)

interaction with reuptake inhibitors (‘serotonin syndrome’)

effects in MAO outlast clearance of drug

35
Q

how do antidepressants affect diet?

A

they inhibit MAO so have huge dietary restrictions
• cannot breakdown tyramine in food
• cheese, red wine, anchovies

36
Q

selective and reversible MAOIs

A

selective
• fewer side effects
• less stimulant
• lower efficacy

reversible
• decrease interaction with other antidepressants
• lower efficacy

37
Q

monoamine reuptake inhibitor antidepressants

A

tricyclic antidepressants (TCAs)

selective serotonin reuptake inhibitors (SSRIs)

NA reuptake inhibitors (NARI)

serotonin and NA reuptake inhibitor (SNRI)

38
Q

what do monoamine reuptake inhibitors do?

A

precent removal of transmitter from the synaptic cleft

levels of transmitter in the cleft increase

magnitude and duration of receptor activation is increased

39
Q

what do TCAs do?

A

inhibit reuptake of 5-HT and NA

related chemical structures 
similar side effects:
• H1 antagonism - sedation 
• mACh antagonists - dry mouth
• alpha-1 antagonism - postural hypotension
40
Q

what do SSRIs do?

A

inhibit reuptake of 5-HT selectively

fewer side effects than TCAs

not more effective than TCAs

41
Q

the serotonin syndrome

A

MAOI + reuptake inhibitor (TCA or SSRI)

synergistic increase in synaptic 5-HT provokes malignant hyperthermia

most MAOIs are irreversible
many SSRIs have long half-lives

must be a long wash out between different drugs

42
Q

current theories to explain delayed antidepressant action

A

postsynaptic receptor adaptation

autoreceptors desensitisation

synaptic remodelling

43
Q

postsynaptic receptor adaptation: to explain delayed antidepressant action

A

elevation of synaptic levels of transmitter cause desensitisation of receptors

amount of receptors decrease - decreased effect

this desensitisation is crucial in the therapeutic response

44
Q

desensitisation of auto receptors: to explain delayed antidepressant action

A

antidepressants inhibit firing and terminal release via auto receptors
• synaptic 5-HT levels don’t increase

autoreceptors desensitise firing
• terminal release is restored
• synaptic 5-HT levels elevated

45
Q

synaptic remodelling: to explain delayed antidepressant action

A

5-HT is a trophic factor - role of development of CNS

antidepressants cause increase in 5-HT

increased 5-HT causes synaptic remodelling which takes time
• spines grow on the postsynaptic neurone on the dendrites
• connectivity and output of neurones increased

Pharmacology (24 decks)

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