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brs (phase 1b) > (pharm) pharmacology of depression > Flashcards

(pharm) pharmacology of depression Flashcards

1
Q

what five drugs are commonly prescribed to treat depression?

A

sertraline

citalopram

fluoxetine

venlafaxine

mirtazapine

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2
Q

explain the primary mechanism of action of sertraline

A

inhibition of serotonin transporter prevents serotonin reuptake from synapse

= accumulation of serotonin in synapse

= increased serotonin in CNS regulates mood, personality, and wakefulness

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3
Q

what is the drug target for sertraline?

A

serotonin transporter

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4
Q

what are the main side effects of sertraline?

A

gastrointestinal effects (nausea/diarrhoea)

sexual dysfunction

anxiety

insomnia

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5
Q

aside from the serotonin transporter, what does sertraline also mildly inhibit?

A

dopamine transporter

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6
Q

which liver enzyme does sertraline inhibit at high doses (150mg)?

A

partial inhibition of CYP2D6

enzyme involved in the metabolism of xenobiotics in the body

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7
Q

how can sertraline treatment be discontinued?

A

must be gradually decreased on discontinuation

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8
Q

explain the mechanism of action of citalopram

A

inhibition of serotonin transporter prevents serotonin reuptake from synapse

= accumulation of serotonin in synapse

= increased serotonin in CNS regulates mood, personality, and wakefulness

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9
Q

what is the drug target for citalopram?

A

serotonin transporter

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10
Q

what are the side effects of citalopram?

A

gastrointestinal effects (nausea/vomiting)

sexual dysfunction

anxiety

insomnia

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11
Q

what does citalopram act as a mild antagonist for?

A

muscarinic and histamine (H1) receptors

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12
Q

how can citalopram treatment be discontinued?

A

must be gradually decreased on discontinuation

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13
Q

which liver enzyme metabolises citalopram?

A

CYP2C19

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14
Q

explain the mechanism of action of fluoxetine

A

inhibition of serotonin transporter prevents serotonin reuptake from synapse

= accumulation of serotonin in synapse

= increased serotonin in CNS regulates mood, personality, and wakefulness

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15
Q

what is the drug target for fluoxetine?

A

serotonin transporter

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16
Q

what are the side effects of fluoxetine?

A

gastrointestinal effects (vomiting, nausea)

sexual dysfunction

anxiety

insomnia

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17
Q

what does fluoxetine act as a mild antagonist for?

A

5HT2A and 5HT2C receptors

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18
Q

which liver enzymes are inhibited by fluoxetine?

A

complete inhibition of CYP2D6 and significant inhibition of CYP2C19

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19
Q

explain the mechanism of action of venlafaxine

A

more potent inhibitor of serotonin reuptake than noradrenaline reuptake

increased noradrenaline in the CNS regulates emotions and cognition

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20
Q

what are the drug targets for venlafaxine?

A

serotonin transporter

noradrenaline transporter

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21
Q

what are the side effects of venlafaxine?

A

gastrointestinal effects (nasuea, diarrhoea)

sexual dysfunction

anxiety

insomnia

hypertension (at higher doses)

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22
Q

how can venlafaxine treatment be discontinued?

A

must be gradually decreased on discontinuation

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23
Q

explain the mechanism of action of mirtazapine

A

antagonises central presynaptic alpha-2-adrenergic receptors = increased release of serotonin and noradrenaline

antagonises central 5HT2 receptors = so 5HT1 receptors are unopposed = anti-depressant effects

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24
Q

what is the drug target of mirtazapine?

A

alpha-2 receptors

5HT2 receptors

25
Q

what are the side effects of mirtazapine?

A

weight gain

sedation

(low probability of) sexual dysfunction

26
Q

what can taking mirtazapine exacerbate potentially?

A

can possibly exacerbate REM sleep behaviour disorder

27
Q

what tool is used to screen for depression?

A

PHQ-9 (patient health questionnaire-9)

28
Q

what is PHQ-9?

A

patient health questionnaire 9

= tool used to screen for depression in suspected individuals in a primary care setting

29
Q

what does major depressive disorder incorpoate?

A

minor, moderate and severe depression

30
Q

what are the therapeutic objectives for a patient with a PHQ-9 score of 14?

A

PHQ-9 of 14 = indicative of moderate depression

1) alleviate symptoms of depression (e.g. disturbed sleep, impaired appetite, low mood)
2) reduce the impact of subsequent functional impairments (i.e. strained relationships, job)

31
Q

what are the three most commonly prescribed SSRIs?

A
  • sertraline
  • citalopram
  • fluoxetine
32
Q

why are SSRIs preferentially prescribed compared to other antidepressants?

A

SSRIs have fewer side effects compared to other anti-depressants

= as they are more selective with their target site of action

33
Q

what is the primary mechanism of action of SSRIs?

A

target =
serotonin transporter

location =
pre-synaptic neurone

effect =

  • inhibit the action of the 5HT transporter so the synaptic concentration of serotonin remains high
  • increased synaptic serotonin acts more on the 5HT receptors
  • increase regulation of mood + wakefulness
34
Q

why can citalopram not be prescribed in patients on erythromycin?

A

both medications prolong the QT interval

(cannot take two or more drugs simultaneously that prolong the QT interval)

risk factors for prolonged QT interval = increased age, female sex, cardiac disease, metabolic disturbances (e.g. hypokalaemia)

35
Q

what impact does increasing SSRI dose have on the therapeutic effect?

A

increasing SSRI dose increases therapeutic effect up until 30mg approximately

after which it plateaus and at higher doses of serotonin, it causes a decrease in therapeutic effect

36
Q

what impact does increasing SSRI dose have treatment dropouts?

A

increasing SSRI dose exponentially increases the number of dropouts from treatment

= due to the increasing severity of the adverse effects

37
Q

if we assume that the anti-depressant effects of SSRIs are solely due to their action at the serotonin transporter, how do we explain the plateau in the therapeutic effect with increasing dose?

A

eventually, at some point, all the serotonin produced in the pre-synaptic neurone has been maximally released

= no more serotonin is available to be released

38
Q

compare the drug targets for venlafaxine and mirtazapine

A

venlafaxine = serotonin + noradrenaline transporter

mirtazapine = alpha-2 adrenergic autoreceptors + 5HT2/3 receptors + H1 receptors

39
Q

why are patients weaned off SSRIs first before starting new anti-depressants?

A

when deciding to stop SSRI prescriptions, patients need to slowly decrease dose to nothing

= risk of drug interactions, serotonin syndrome, withdrawal symptoms, relapse

40
Q

what does suddenly stopping SSRI prescriptions risk?

A

increased risk of serotonin syndrome, withdrawal symptoms, relapse and drug interactions

41
Q

how are the risks of stopping SSRIs suddenly avoided?

A

washout is required before starting a new drug

= dose of SSRI is gradually decreased

42
Q

what is a washout period?

A

the waiting time of a few days or weeks after stopping the old drug before starting the new one

= lets your body clear the old drug out of your system

43
Q

why is a washout period important?

A

lets your body clear the old drug out of your system

44
Q

what happens once the washout period is over?

A

usually you start with a low dose of the new drug

45
Q

what is the main side effect of venlafaxine?

A

hypertension

at high doses

46
Q

what are the adernergic effects of venlafaxine and at which doses do they appear?

A

at 150mg/day = adrenergic effects first appear

at 300mg/day =
apparent increase in blood pressure and increased heart rate

47
Q

what is the main side effect of mirtazapine?

A

mirtazapine modestly suppressREMsleep whilst still having a beneficial impact on sleep continuity and duration (due to its anti-histaminergic effects)

= can be good for people w depression suffering from sleep disturbance

48
Q

list the possible drug targets for mirtazapine

A

1) histamine H1 receptor
2) alpha-2 adrenergic receptor
3) 5HT2 receptor
4) 5HT3 receptor

49
Q

describe the binding affinity of mirtazapine to each of its binding sites

A

from highest to lowest affinity:

1) histamine H1 receptor
2) alpha-2 adrenergic receptor
3) 5HT2 receptor
4) 5HT3 receptor

50
Q

what is the effect of mirtazapine binding to the H1 histamine receptor?

A

sedation

off-target effects

51
Q

what is the effect of mirtazapine binding to the alpha-2 adrenergic receptor?

A

anti-depressant effect

on-target effect

52
Q

what is the effect of mirtazapine binding to the 5HT2 receptor?

A

anti-depressant effect

on-target effect

53
Q

what is the effect of mirtazapine binding to the 5HT3 receptor?

A

anti-emetic effect

off-target effect

54
Q

what are the off-target effects of mirtazapine and how do they come about?

A

effects = sedation (H1) and anti-emetic effects (5HT3)

highest binding affinity = increased risk of off target effects at low doses when mirtazapine binds to H1 or 5HT3 receptors

55
Q

what dose of mirtazapine is required to induce the sedative effect of mirtazapine?

A

sedation effect = histamine H1 receptor = highest binding affinity

= so lowest dose required for sedative effect (better, undisturbed sleep)

56
Q

what dose of mirtazapine is required to induce the anti-emetic effect of mirtazapine?

A

anti-emetic effect = 5HT3 receptor = lowest binding affinity

= so higher dose required for anti-emetic effect

57
Q

which side effect of mirtazapine would be induced first at a low dose and why?

A

at low doses, greatest impact on H1 receptors to which they have the highest binding affinity (higher than serotonergic receptors too)

= mirtazapine preferentially blocks the histamine receptor over the serotonergic ones at low doses

58
Q

what is the impact/main side effect of mirtazapine at low doses and why?

A

preferentially blocks the histamine H1 receptor over the alpha-2 adrenergic receptor (next highest binding affinity)

so main side effect = sedation

= increased duration of sleep + increased sedation at low doses

59
Q

what happens to the sedating effect of mirtazapine at higher doses?

A

at higher doses, the antihistamine effect of mirtazapine is offset by its increased action in terms of noradrenergic transmission (alpha-2 adrenergic receptor)

= reduces sedating effect overall

brs (phase 1b) (71 decks)

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