(pharm) pharmacology of depression Flashcards
what five drugs are commonly prescribed to treat depression?
sertraline
citalopram
fluoxetine
venlafaxine
mirtazapine
explain the primary mechanism of action of sertraline
inhibition of serotonin transporter prevents serotonin reuptake from synapse
= accumulation of serotonin in synapse
= increased serotonin in CNS regulates mood, personality, and wakefulness
what is the drug target for sertraline?
serotonin transporter
what are the main side effects of sertraline?
gastrointestinal effects (nausea/diarrhoea)
sexual dysfunction
anxiety
insomnia
aside from the serotonin transporter, what does sertraline also mildly inhibit?
dopamine transporter
which liver enzyme does sertraline inhibit at high doses (150mg)?
partial inhibition of CYP2D6
enzyme involved in the metabolism of xenobiotics in the body
how can sertraline treatment be discontinued?
must be gradually decreased on discontinuation
explain the mechanism of action of citalopram
inhibition of serotonin transporter prevents serotonin reuptake from synapse
= accumulation of serotonin in synapse
= increased serotonin in CNS regulates mood, personality, and wakefulness
what is the drug target for citalopram?
serotonin transporter
what are the side effects of citalopram?
gastrointestinal effects (nausea/vomiting)
sexual dysfunction
anxiety
insomnia
what does citalopram act as a mild antagonist for?
muscarinic and histamine (H1) receptors
how can citalopram treatment be discontinued?
must be gradually decreased on discontinuation
which liver enzyme metabolises citalopram?
CYP2C19
explain the mechanism of action of fluoxetine
inhibition of serotonin transporter prevents serotonin reuptake from synapse
= accumulation of serotonin in synapse
= increased serotonin in CNS regulates mood, personality, and wakefulness
what is the drug target for fluoxetine?
serotonin transporter
what are the side effects of fluoxetine?
gastrointestinal effects (vomiting, nausea)
sexual dysfunction
anxiety
insomnia
what does fluoxetine act as a mild antagonist for?
5HT2A and 5HT2C receptors
which liver enzymes are inhibited by fluoxetine?
complete inhibition of CYP2D6 and significant inhibition of CYP2C19
explain the mechanism of action of venlafaxine
more potent inhibitor of serotonin reuptake than noradrenaline reuptake
increased noradrenaline in the CNS regulates emotions and cognition
what are the drug targets for venlafaxine?
serotonin transporter
noradrenaline transporter
what are the side effects of venlafaxine?
gastrointestinal effects (nasuea, diarrhoea)
sexual dysfunction
anxiety
insomnia
hypertension (at higher doses)
how can venlafaxine treatment be discontinued?
must be gradually decreased on discontinuation
explain the mechanism of action of mirtazapine
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
what is the drug target of mirtazapine?
alpha-2 receptors
5HT2 receptors
what are the side effects of mirtazapine?
weight gain
sedation
(low probability of) sexual dysfunction
what can taking mirtazapine exacerbate potentially?
can possibly exacerbate REM sleep behaviour disorder
what tool is used to screen for depression?
PHQ-9 (patient health questionnaire-9)
what is PHQ-9?
patient health questionnaire 9
= tool used to screen for depression in suspected individuals in a primary care setting
what does major depressive disorder incorpoate?
minor, moderate and severe depression
what are the therapeutic objectives for a patient with a PHQ-9 score of 14?
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)
what are the three most commonly prescribed SSRIs?
- sertraline
- citalopram
- fluoxetine
why are SSRIs preferentially prescribed compared to other antidepressants?
SSRIs have fewer side effects compared to other anti-depressants
= as they are more selective with their target site of action
what is the primary mechanism of action of SSRIs?
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
why can citalopram not be prescribed in patients on erythromycin?
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)
what impact does increasing SSRI dose have on the therapeutic effect?
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
what impact does increasing SSRI dose have treatment dropouts?
increasing SSRI dose exponentially increases the number of dropouts from treatment
= due to the increasing severity of the adverse effects
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?
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
compare the drug targets for venlafaxine and mirtazapine
venlafaxine = serotonin + noradrenaline transporter
mirtazapine = alpha-2 adrenergic autoreceptors + 5HT2/3 receptors + H1 receptors
why are patients weaned off SSRIs first before starting new anti-depressants?
when deciding to stop SSRI prescriptions, patients need to slowly decrease dose to nothing
= risk of drug interactions, serotonin syndrome, withdrawal symptoms, relapse
what does suddenly stopping SSRI prescriptions risk?
increased risk of serotonin syndrome, withdrawal symptoms, relapse and drug interactions
how are the risks of stopping SSRIs suddenly avoided?
washout is required before starting a new drug
= dose of SSRI is gradually decreased
what is a washout period?
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
why is a washout period important?
lets your body clear the old drug out of your system
what happens once the washout period is over?
usually you start with a low dose of the new drug
what is the main side effect of venlafaxine?
hypertension
at high doses
what are the adernergic effects of venlafaxine and at which doses do they appear?
at 150mg/day = adrenergic effects first appear
at 300mg/day =
apparent increase in blood pressure and increased heart rate
what is the main side effect of mirtazapine?
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
list the possible drug targets for mirtazapine
1) histamine H1 receptor
2) alpha-2 adrenergic receptor
3) 5HT2 receptor
4) 5HT3 receptor
describe the binding affinity of mirtazapine to each of its binding sites
from highest to lowest affinity:
1) histamine H1 receptor
2) alpha-2 adrenergic receptor
3) 5HT2 receptor
4) 5HT3 receptor
what is the effect of mirtazapine binding to the H1 histamine receptor?
sedation
off-target effects
what is the effect of mirtazapine binding to the alpha-2 adrenergic receptor?
anti-depressant effect
on-target effect
what is the effect of mirtazapine binding to the 5HT2 receptor?
anti-depressant effect
on-target effect
what is the effect of mirtazapine binding to the 5HT3 receptor?
anti-emetic effect
off-target effect
what are the off-target effects of mirtazapine and how do they come about?
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
what dose of mirtazapine is required to induce the sedative effect of mirtazapine?
sedation effect = histamine H1 receptor = highest binding affinity
= so lowest dose required for sedative effect (better, undisturbed sleep)
what dose of mirtazapine is required to induce the anti-emetic effect of mirtazapine?
anti-emetic effect = 5HT3 receptor = lowest binding affinity
= so higher dose required for anti-emetic effect
which side effect of mirtazapine would be induced first at a low dose and why?
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
what is the impact/main side effect of mirtazapine at low doses and why?
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
what happens to the sedating effect of mirtazapine at higher doses?
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
