2. Antidepressants Flashcards
what are the 8 main classes of antidepressants?
- SSRI’s
- SNRI’s
- SARI’s (trazodone)
- TCA’S
- NDRI (bupropion)
- NaSSA (mirtazipine)
- MAOI
- multi-modal
NE’s action can be terminated through multiple mechanisms: dopamine can be transported out of the synaptic cleft and back into the presynaptic neutron via the ______________________ where it may be repackaged for future use
norepinephrine transporter
NE’s action can be terminated through multiple mechanisms: norepinephrine can be broken down extracellularly via the enzyme _____
COMT
NE’s action can be terminated through multiple mechanisms: these enzymes that can break down norepinephrine which are present in the mitochondria both with the presynaptic neutron and in other cells, including neurone glia
MAO-A and MAO-B
a presynaptic receptor on the norepinephrine neuron where NE binds and causes less production of NE?
alpha2 autoreceptor
what is the result if NE binds to and inhibits a postsynaptic alpa1 receptor
orthostasis
what is the result if NE binds to and activates a postsynaptic alpha2 receptor in the prefrontal cortex?
activation and insomnia
what is the result if NE binds to and activates a postsynaptic beta1 receptor in the prefrontal cortex?
mood regualtion; this is our target because beta1 is what is causing the issue in depression
if beta1 is activated in other parts of the body, may cause tremors and increased HR
what is the amino acid precursor for serotonin?
tryptophan
serotonins action is terminated by the enzymes _______ and ______ outside the neuron and ______ within the neuron when it is present in high concentrations
outside the neutron - MAO-A and MAO-B
inside the neutron - MAO-B
this clears serotonin out of the synapse and back into the presynaptic neuron
SERT
what are the 4 receptors that are present on the serotonin presynaptic neuron
5HT 1B/D autoreceptors brake
5HT 1A autoreceptors brake
alpha2 heteroreceptor brake
alpha1 heteroreceptor accelerator
what is the result when the 5HT 1a post-synaptic receptor is activated
mood regualtion and antidepressant efficacy therefore this is the target of drug action
what is the result when the 5HT 2a post-synaptic receptor is activated
5 A side effects
A - Agitation
A - Anxiety
A - Akathisia (restlessness)
A - Awake (insomnia)
A - Asexual (sexual dysfunction)
what is the result when the 5HT3 receptor is activated
headache and GI upset
(the migraine receptor)
what is the result when the 5HT 2C receptor is activated
weight gain
when an antidepressant is introduced, how quickly do neurotransmitter levels change, time to see a clinical effect and time for neurotransmitter receptors to be desensitized
- amount of NT changes rapidly
- time to see clinical effect and downregulation of neurotransmitter receptors is delayed
*known as the monoamine receptor down regulation hypothesis
true or false: when an antidepressant is introduced there is a lag time to see a clinical effect and side effects
false - lag time to see clinical effect but side effects can be seen right away but usually decrease overtime
true or false: upregualtion of postsynaptic monoamine neurotransmitter receptors results in depression
true
explain how antidepressants work with regards to the monoamine receptor hypothesis
monoamine receptor hypothesis: depression is caused by up regulation of monoamine receptors
when an antidepressant blocks a monoamine reuptake pump, this causes more NT to accumulate in the synapse.
the increased availability of NT causes the receptors to down regulate. the time for this to happen is consistent with the delayed clinical affects of antidepressants and the development of tolerance to antidepressant side effects
what are the 3 targets for drug action in the presynaptic/synaptic region by increasing the amount of NT available in the cleft
- block the reuptake pump
- block/cut the auto/heteroreceptor brakes
- inactivate the degrading enzymes
if this receptor is activated in the 5HT system, a patient may experience anxiety, akathisia, agitation, insomnia and/or sexual dysfunction
5HT2a
if this receptor is blocked in the 5HT system, a patient may experience headache and GI side effects
5HT3
if this receptor is blocked in the 5HT system, a patient may experience weight gain
5HT2c
if this receptor is blocked in the noradrenergic system, a patient may experience orthostasis
alpha 1
if this receptor is blocked in the histaminic system, a patient may experience sedation and weight gain
H1
if this receptor is blocked in the cholinergic system, a patient may experience dry mouth, dry eyes, blurry vision, constipation, urinary retention, confusion and delirium
M1
if this receptor is blocked in the cholinergic system, a patient may experience T2DM and impaired glucose tolerance (IGT)
M3
which TWO classes of antidepressants antagonize the serotonin reuptake pump as their main MOA?
1.selective serotonin reuptake inhibitors (SSRI’s)
- citalopram
- escitalopram
- fluoxetine
- fluvoxamine
- paroxetine
- sertraline
- serotonin antagonist reuptake inhibitors -> serotonin 2A antagonist/reuptake inhibitor
- trazodone
the serotonin reuptake inhibitor (SRI) portion of this drug molecule inserts into the serotonin reuptake pump, blocking it and causing an antidepressant effect
SSRI
SSRI’s can lead to increased 5-HT in the synapse which can then bind to a number of presynaptic receptors. what are these postsynaptic receptors and what effect will be seen if serotonin binds to them?
5HT1a - target receptor; causes downregulation of receptors and therefore treats the depression
5HT2a - “5A’s” - Agitation, Anxiety, Akathisia, Asexual, Awake
5HT3 - headache & GI upset
true or false: trazodone acts on both the presynaptic and post synaptic neuron
true
how does trazodone work on the presynaptic neuron?
the serotonin reuptake inhibitor (SRI) portion of trazodone is inserted into the serotonin reuptake pump and blocks it
how does trazodone work on the postsynaptic neuron?
the 5HT2a portion of trazodone is inserted into the 5HT2a receptor and the 5HT2c potion of trazodone is inserted into the 5HT2c receptor and antagonism of these receptors occurs
true or false: the serotonin retake actions of trazodone are more potent than the 5HT2a and 5HT2c antagonism properties
false - 5HT2a antagonism is the most potent
true or false: 5HT2A associated side effects are commonly seen with trazodone (the 5A’s)
false - remember we see trazodone used a lot for sleep therefore don’t get insomnia (Awake is one of the 5A’s); don’t get these because the 5HT2a receptor is blocked by trazodone, therefore 5HT in the cleft can’t bind to it
true or false: trazodone is commonly used for depression
false
what is a common side effect of trazodone associated with H1 antagonism?
sedation
what is a side effect of trazodone associated with alpa1 antagonism?
orthostasis, dizziness, reflex tachycardia
true or false: 5HT3 associated side effects (headache, GI upset / migraine like effects) are seen with trazadone
true - trazodone does not block 5HT3 therefore its available to 5HT to bind to
which TWO classes of antidepressants antagonize the serotonin & norepinephrine reuptake pump as their main MOA?
- serotonin & norepinephrine reuptake inhibitors
- venlafaxine
- duloxetine
- desvenlafaxine
- levomilnacipran - TCA’s
- amitriptyline
- imipramine
- desipramine
true or false: all TCA’s block reuptake of norepinephrine and are antagonists of histamine 1, alpha 1 adrenergic, and muscarinic cholinergic receptors
true
true or false: all TCA’s block voltage sensitive sodium channels
true
true or false: all TCA’s are potent inhibitors of the serotonin reuptake pump
false - some are
true or false: all TCA’s are antagonists of serotonin 2A and 2C receptors
false - some are
what is the MOA of TCA’s?
blocks the serotonin and norepinephrine reuptake pumps (SERT and NET) which increase the amount of 5HT and NE available to bind which leads to downregulation of receptors and anti-depressant effect
what reuptake pump do nortriptyline, desipramine and protriptyline have a higher affinity for?
NRI > SRI
what reuptake pump does clomipramine have a higher affinity for?
SRI > NRI <- know this!!
therefore it is essentially a serotonin reuptake inhibitor and it usually used to treat OCD due to this property
what reuptake pump do amitriptyline and imipramine have a higher affinity for?
NRI = SRI
TCA’s can insert their antihistamine (H1) portion into histamine receptors and cause what side effects?
sedation and weight gain
TCA’s can insert their anticholinergic/antimuscarinic (M1) portion into acetylcholine receptors and cause what side effects?
can’t see (blurry vision), can’t pee (urinary retention), can’t spit (dry mouth), can’t sh*t (consitpation)
+ confusion and drowsiness
TCA’s can insert their alpha-adrenergic antagonist portion into the alpha-1 adrenergic receptor and cause what side effects?
dizziness, drowsiness, orthostasis and reflex tachycardia
what is the MOA of SNRI’s
the SRI portion of the SNRI molecule is inserted into the serotonin reuptake pump therefore blocking it, and same for the NRI and norepinephrine reuptake pump
why are SNRI’s known as a “smooth TCA”
SNRI’s work the same as a TCA as they both block SERT and NET, but SNRI’s don’t affect the H1, M1 and alpha1 receptors therefore SNRI’s don’t produce the side effects associated with those receptors and TCA’s do
which SNRI has dose dependent pharmacology
venlafaxine
how does venlafaxine act at lower doses (e.g. 750-150 mg)?
SRI with fewer drug interactions
how does venlafaxine act at moderate doses (e.g. 150-300 mg)?
SRI + NRI
how does venlafaxine act at higher doses (e.g. 300-375 mg)?
SRI + NRI + DRI
(like using an SSRI + bupropion)
venlafaxine is converted to its active metabolite ___________ by CYP 2D6
desvenlafaxine
true or false: desvenlafaxine works like venlafaxine in that it inhibits reuptake of serotonin (SRI) and norepinephrine (NRI), but its SRI actions are greater relative to its NRI actions compared to venlafaxine
false - its NRI actions are greater relative to its SRI actions compared to venlafaxine
which antidepressant antagonizes the norepinephrine and dopamine reuptake pumps?
NDRI’s
- buproprion
true or false: bupropion has an affect on serotonin
false
therefore it is sometimes a nice add on to an SSRI
what is the MOA of bupropion?
the NRI portion and the DRI portion of the NDRI drug molecule are inserted into their respective reuptake pumps. both reuptake pumps are blocked and the drug mediates an antidepressant effect
what are some side effects that may be seen with bupropion due to an increase in norepinephrine in the synapse?
postsynaptic alpha2 agonism -> activation, agitation, insomnia
what are some side effects that may be seen with bupropion due to an increase in dopamine in the synapse?
pro-sexual (b/c no serotonin involvement)
antiparkinsonian effect (good for someone with depression AND Parkinson’s)
could aggravate psychosis
which antidepressant antagonizes a presynaptic auto/heteroreceptor (cuts the brake)
NaSSA (noradrengeric and specific serotonergic antidepressant)
- mirtazepine
what is mirtazepines main therapeutic action?
alpha 2 antagonism
what serotonin receptors does mirtazapine block?
5HT2A, 5HT2C and 5HT3
- serotonin in synapse cannot bind to these therefore increased chance that serotonin will bind to receptor we want that helps with mood regulations (5HT1A) and then receptors will down regulate
explain how mirtazapine acts as a serotonin and NE disinhibitor
NE neuron is disinhibited at all of its axon terminals because mirtazapine is blocking the presynaptic alpha 2 auto receptors (brakes) casing more NE release
serotonin release in enhanced by NE in two ways:
1. alpha 2 antagonists (mirtazipine) step on the 5HT accelerator when NE stimulates alpha 1 receptors on 5HT neuron
2. alpha 2 antagonists (mirtazipine) cut the 5HT brakes when alpha 2 presynaptic heteroreceptors are blocked on the 5HT neuron
true or false: mirtazipine is an agonist of H1 receptors
false - antagonizes
when mirtazipine blocks H1 receptors it can cause anxiolytic actions and possibly reduce insomnia, but it may also contribute to weight gain and daytime drowsiness
which antidepressants inactivate the degrading enzyme monoamine oxidase?
MOAI’s
which MAOI’s are irreversible?
a) tranylcypromine
b) phenelzine
c) moclobemide
a and b
which MAOI’s are reversible?
a) tranylcypromine
b) phenelzine
c) moclobemide
c
therefore serotonin or norepinephrine can come along and bump this off
is there a risk of dangerous vasoconstriction and elevated blood pressure with irreversible or reversible MOAI
irreversible
b/c tyramine is releasing NE and the degrading enzyme is inhibited by MAOI therefore there can be a very large accumulation of NE
why doesn’t reversible MAOI’s have a risk of high blood pressure and vasoconstriction
because the NE produced by tyramine can displace the reversible MAOI which will allow for normal destruction of the extra NE that may build up
what are some side effects that may be seen with MAOI’s due to an increase in norepinephrine in the synapse?
post-synaptic alpha 2 agonism - activation, agitation and insomnia
what are some side effects that may be seen with MAOI’s due to an increase in serotonin in the synapse?
post-synaptic 5HT2 agonism (5A’s) - agitation, anxiety, akathisia, awake, asexual
post-synaptic 5HT3 agonism - headache & GI upset
what foods should be avoided when taking an MAOI
foods high in tyramine (e.g. aged cheeses, aged and cured meats, tap beer, sauerkraut, soy inlcuded tofu)
what is the recommended washout period for an irreversible MOAI to another antidepressant?
14/7
includes a few days to clear the drug and 7-10 days to make new MAO enzyme
what is the recommended washout period for a reversible MAOI to another antidepressant?
2-3 days
only need to washout the drug because you can reuse the MAO enzyme
how does multi-modal agents (e.g. vortioxetine) increase 5HT in the synapse?
presynaptic somatodendritic 5HT1a (accelerator) agonist
true or false: multi modal agents are 5HTd antagonists
true
true or false: multimodal agents are 5HT3 agonists therefore side effects include headache and GI upset with these agents
false - 5HT3 antagonist
