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CPTP 3 > 3.3 Antidepressants > Flashcards

3.3 Antidepressants Flashcards

1
Q

Why does the antihypertensive reserpine induce depression?

A

Because it depletes monoamine vesicles

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2
Q

Why does the antiTB drug iproniazid improve mood in TB patients?

A

Blocks MAO, involved in the breakdown of monoamines

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3
Q

What causes depression?

A

‘Depression is due to a deficit in central monoamine (5‑HT and NA) neurotransmission.’

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4
Q

What evidence is there for depression being due to deficit in central monoamine?

A

• Antidepressant drugs increase monoamines and elevate mood
• Reserpine inhibits monoamine storage and lowers mood
• Inhibition of 5-HT synthesis lowers mood
Changes in monoamine receptors in PET studies in depressed patients

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5
Q

What evidence is there against the current definition of depression?

A

Cocaine inhibits NA uptake and is not antidepressant

Little evidence of lowered monoamines or metabolites in patients with depression

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6
Q

How is 5-HT synthesised?

A

Tryptophan
5-HTP
5-HT

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7
Q

How is 5-HT stored?

A

Compartmentalised into vesicle for protection from cytosolic enzymes and ready for exocytosis

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8
Q

Which receptors are related to 5-HT?

A

5-HT2A, 5-HT1A, 5-HT2C, 5-HT1P (presynaptic and postsynaptic receptor)

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9
Q

How is 5-HT terminated?

A

Re-uptake by SERT transporter then recycled by vesicles or degraded by MAO

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10
Q

Which anti-depressants block re-uptake of NA or 5-HT?

A

Tricyclic antidepressants - TCAs
Selective serotonin re-uptake inhibitors - SSRIs
SNRIs & NARIs
These increase duration and concentration of transmitter

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11
Q

Give example TCAs…

A

amitriptyline, imipramine, lofepramine

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12
Q

What clinical limitations are there of TCAs…

A

Delayed onset - 2-3 weeks
Affinity for other post synaptic receptors
• M1 receptor antagonism-dry mouth blurred vision, constipation, urinary retention
• H1 receptor antagonism-sedation, weight gain
• α1-adrenoceptor antagonism-postural hypotension
Side effects immediate, therapeutic effects delayed - feel worse before feel better- poor compliance and poor overall therapeutic efficacy
Cardiotoxic and potentially fatal in overdose

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13
Q

What is the clinical use of TCAs…

A

Useful for
• Severe, treatment resistant depression and TCA are cheap!
Not used in
• Elderly, young - more sensitive to side effects
• Cardiac patients (increase chance of conduction abnormalities)
• Suicidal patients (overdose)
• Drivers (sedation)
Workers (sedation)

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14
Q

Give examples of SSRI, SNRI and NARI… (2nd generation antidepessants)

A

• SSRI: selective serotonin reuptake inhibitor (fluoxetine)
• SNRI: serotonin/ noradrenaline reuptake inhibitor (venlafaxine)
NARI noradrenaline reuptake inhibitor (reboxetine)

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15
Q

What are the benefits of the 2nd generation anti-depressants…

A

Selective for 5-HT or NA transporter and do not have affinity for postsynaptic receptors (fewer side effects)

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16
Q

Which anti-depressants are most effective?

A

TCAs then SSRIs then SNRIs

however TCAs have extreme amount of side effects

17
Q

What are the side effects of SSRIs?

A

• Precipitate anxiety
• Nausea
• Sexual dysfunction (impotence)
• Gastrointestinal (nausea, constipation)
• Weight gain
• Drug interactions with other antidepressant drugs
• Cytochrome P450 inhibition
• CYP1A2, CYP2D6 and CYP3A4
Sedation or anticholinergic side effects limited

18
Q

What is the function of VMAT 2?

A

Transports transmitter into vesicles

19
Q

What is the function of MAO?

A

MAO will metabolise transmitter outside the vesicles

20
Q

What do MAO inhibitors do?

A

Decrease intraneuronal breakdown
Increased vesicle content
Increase release

21
Q

What are the two isoforms of MAO

A 
MAOa = breaks down 5-HT/NA
MAOb = breaks down DA
22
Q

What did old MAOs used to do?

A

Older MAOIs blocked both isoforms irreversibly
(e.g. tranylcypramine, phenelzine)
Stimulant effects, - blocking B
Dangerous in overdose - blockin B

23
Q

What how do new MAOs work?

A

New MAOIs selective for MAOA, reversable RIMA
(e.g. moclopemide)
Less stimulant
Safer

24
Q

what is the MAO and cheese effect?

A

MAO in gut and periphery breaks down dietary amines, if combine MAOI with diet high in amines leads to hypertensive crisis

25
Q

What is serotonin syndrome?

A

MAO & SSRIs
Hyperthermia, confusion hypertensive crisis
Particularly important for SSRIs with long elimination half life (e.g. fluoxetine)
MAOI to Fluoxetine 2 weeks break
Fluoxetine to MAOI 5 weeks break

26
Q

What is the affinity of the atypical antidepressants like?

A

Have affinity for a range of monoamine transporters and receptors

27
Q

Give examples of atypical antidepressants?

A

Mirtazepine
Nefazodone
Mianserin

28
Q

How can you increase 5-ht synthesis and is it effective?

A

• Increase precursor availability
• Tryptophan load, in theory should improve mood
• Not clinically effective
• However:
plasma tryptophan levels may be important in therapeutic response of other antidepressants treatments

29
Q

What increase 5-HT release?

A

• Releasing agent
• MDMA (ecstasy)
Impractical on account of long term neurotoxicity

30
Q

Why does a delayed onset of anti-depressants occur?

A

• 5-HT is increased acutely but produces its therapeutic effect by a trophic action resulting in synaptic remodelling
SSRIs cause trophism and increase trophics factor in experimental animal - strengthening of the synapse - synaptic remodelling

31
Q

How does increase 5-HT in the DRN cause delayed onset?

A 
SSRIs block 5HT transporter in DRN 
5HT levels in the DRN increase 
5-HT1a auto receptors are activated 
Firing is inhibited
Terminal release is inhibited - until 2-3 weeks when the receptors becomes desensitised 
5-ht1a antagonists could prevent this
32
Q

What happens to the receptors in the DRN after repeated dosing…

A

5-HT1A receptors are desensitised
Firing is restored
Terminal release is restored
Synaptic 5-ht levels rise

CPTP 3 (5 decks)

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