Antidepressant Pharmacology and Chemistry (L13-L14)

TCAs enhance the functional activity of ____________ and ___________ by blocking the neuronal reuptake of them

NE, 5-HT (Norepinephrine and Serotonin)

TCAs ___________ the functional activity of NE and 5-HT by ___________ the neuronal reuptake of them

enhance, blocking

TCAs enhance the functional activity of NE and 5-HT by blocking the neuronal __________ of them

reuptake

___________ (class) enhance the functional activity of NE and 5-HT by blocking the neuronal reuptake of them

TCAs (ex: Amitriptyline)

MAO-Is inhibit the enzyme MAO

normally, MAO is responsible for the _________ of monoamines such as NE, 5-HT, and dopamine

breakdown (if its inhibited= less broken down= more available)

___________ (class) inhibit the enzyme _______

normally, ________ is responsible for the breakdown of monoamines such as NE, 5-HT, and dopamine

MAO (ex: Phenelzine)

SSRIs block only the reuptake of _________

serotonin (5-HT)

NARIs block only the reuptake of _________

NE (Norepinephrine)

SSRIs only block the __________ of serotonin (5-HT)

reuptake

NARIs only block the __________ of NE (Norepinephrine)

reuptake

SSRIs ________ the reuptake of serotonin (5-HT) only

block

NARIs ________ the reuptake of NE (Norepinephrine) only

block

___________ (class) block only the reuptake of serotonin (5-HT)

SSRIs (ex: fluoxetine, paroxetine)

___________ (class) block only the reuptake of NE (Norepinephrine)

NARIs (ex: reboxetine)

SNRIs block the reuptake of both ________ and _________

NE and 5-HT (similarly to TCAs but w/o all the crazy SEs)

SNRIs block the __________ of both NE and 5-HT

reuptake (similarly to TCAs but w/o all the crazy SEs)

____________ (class) block the reuptake of both NE and 5-HT

SNRIs (ex: venlafaxine ==> similarly to TCAs but w/o all the crazy SEs)

SNRIs block the reuptake of both NE and 5-HT, similar to TCAs but thankfully lacking their anti_________ and anti___________ side effects

antimuscarinic and antihistaminic

SNRIs block the reuptake of both NE and 5-HT, similar to ____________ (class) but thankfully lacking their antimuscarinic and antihistaminic side effects

TCAs

pathophysiology of depression: monoamine hypothesis

deficiency and imbalance of the neurotransmitters

__________ and _________ and their inter-relationship with ___________

5-HT, NE, Dopamine

how quickly do antidepressants work?

during the first week pt may experience mild ______ ______

side effects

how quickly do antidepressants work?

pt may start to feel the medication working within the first ___ weeks

2

how quickly do antidepressants work?

it can take ___-___ weeks to get the full benefit of the medications

most side effects will resolve by week ____

4-8, 4

___________ (class) are used as a last-stitch choice if pts don’t respond to other classes

MAO-Is

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

by blocking MAO enzyme and therefore blocking the breakdown of neurotransmitters, the concentration of neurotransmitters builds up in the ______________ cell

pre-synaptic

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

by blocking MAO enzyme and therefore blocking the breakdown of neurotransmitters, the concentration of neurotransmitters builds up in the pre-synaptic cell

this allows more neurotransmitter to be released into the _________ _________

synaptic cleft

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

MAO-A prefers _________, but also metabolizes _____ and _______

this part is mostly responsible for the antidepressant effect

5-HT, NE, DA

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

MAO-____ prefers 5-HT, but also metabolizes NE and DA

this part is mostly responsible for the antidepressant effect

A

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

MAO-B prefers ______ only

not as responsible for antidepressant effect

DA

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

MAO-____ prefers Dopamine only

not as responsible for antidepressant effect

B

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

Isocarboxazide, Phenelzine, and Tranylcypromide are ___________ (reversible or irreversible)

Selegiline is selective for MAO-B (treats depletion of DA in Parkinson’s)

irreversible (covalent bond)

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

Isocarboxazide, Phenelzine, and Tranylcypromide are irreversible (covalent bond)

Selegiline is __________ for MAO-B (treats depletion of DA in Parkinson’s)

selective (Selegiline is Selective)

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

Isocarboxazide, Phenelzine, and Tranylcypromide are irreversible (covalent bond)

Selegiline is selective for MAO-____

B (treats depletion of DA in Parkinson’s)

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

Isocarboxazide, Phenelzine, and Tranylcypromide are irreversible (covalent bond)

____________ is selective for MAO-B (treats depletion of DA in Parkinson’s)

Selegiline (Selegiline is Selective)

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

_________ effect: severe irreversible/nonselective side effect that can lead to life-threatening HTN

- can come from dietary sources and accumulate

tyramine (cheese, chocolate, wine)

MAO-Is are used as a last-stitch choice if pts don’t respond to other classes

Tyramine effect: severe irreversible/nonselective side effect that can lead to life-threatening _________

- can come from dietary sources and accumulate

HTN

_____________ (class) can have the Tyramine effect: severe irreversible/nonselective side effect that can lead to life-threatening HTN

- can come from dietary sources like cheese, wine, or chocolate and accumulate

MAO-Is

chemistry of MAO-Is: the enzyme __________ the free amino group (-NH2) of the neurotransmitter

oxidizes

chemistry of MAO-Is: the enzyme oxidizes the ______ ________ group of the neurotransmitter

free amino (-NH2)

chemistry of MAO-Is: the enzyme oxidizes the free amino group (-NH2) of the neurotransmitter —> into an unstable ___________ —> then into acids

aldehyde

chemistry of MAO-Is: they actually come from the anti-TB compound Isoniazide but were made more _________ and have better __________

(this was withdrawn d/t CNS stimulation and hepatotoxicity but it was a good idea)

lipophilic, bioavailability

chemistry of MAO-Is: classic structure is two attached N—N

Hydra_____: N—N attached together with a free amino group on the end

Hyrda_____: N—N attached together and next to a carbonyl group

hydrazine, hydrazide

chemistry of MAO-Is: classic structure is two attached N—N

Hydrazide: N—N attached together next to a _________ group

Hydrazine: N—N attached together next to a _________ group

carbonyl (orange), free amine (yellow)

which class are these structures indicative of?

MAO-Is (N—N attached next to free amine or carbonyl)

which of these compounds can lead to life-threatening HTN if taken shortly after the consumption of cheese?

C (cheese= tyramine effect= happens with MAO-Is= structure is N—N)

which of these compounds is an enzyme inhibitor?

C (MAO-I with the structure N—N ==> compounds A and B are reuptake inhibitors)

TCAs interfere with reuptake of both _____ and ______

the cell is recycling neurotransmitters, but TCAs block the channel that takes them back up into the pre-synaptic cell

NE, 5-HT

__________ (class) interfere with reuptake of both NE and 5-HT

the cell is normally constantly recycling neurotransmitters, but ________ block the channel that takes them back up into the pre-synaptic cell

neurotransmitters stay in the synaptic cleft longer which increases the likelihood of them binding to the post-synaptic receptor

TCAs (ex: Amitriptyline)

TCAs interfere with reuptake of both NE and 5-HT

SEs (fewer than MAO-Is, but still not great)

- alpha receptor blocking= ________ _________ and __________

- histamine receptor blocking= sedation

- muscarinic receptor blocking= ___________ effects

- cardiac Na+ channel blocking= antiarrhythmic effect that can lead to cardiac conduction abnormalities

orthostatic hypotension, dizziness, anticholinergic

chemistry of TCAs= three-ring= tri-cyclic

the Ns highlighted in blue are __________

the Ns highlighted in red are __________

tertiary (connected to x3 carbons)

secondary (connected to x2 carbons and x1 hydrogen)

chemistry of TCAs= three-ring= tri-cyclic

this compound has a ________ amine and is therefore more __________ (sedative or stimulatory) since it has a higher affinity to ___________ reuptake transporters

tertiary, sedative, serotonin (SERT)

chemistry of TCAs= three-ring= tri-cyclic

this compound has a ________ amine and is therefore ______ sedative, since it has a _________ affinity to serotonin reuptake transporter

tertiary, more, higher

chemistry of TCAs= three-ring= tri-cyclic

this compound has a ________ amine and is therefore ______ stimulatory, since it has a _________ affinity to serotonin reuptake transporter

tertiary, less, higher

chemistry of TCAs= three-ring= tri-cyclic

this compound has a ________ amine and is therefore ______ sedative, since it has a _________ affinity to norepinephrine reuptake transporter

secondary, less, higher

chemistry of TCAs= three-ring= tri-cyclic

this compound has a ________ amine and is therefore ______ stimulatory, since it has a _________ affinity to norepinephrine reuptake transporter

secondary, more, higher

chemistry of TCAs= three-ring= tri-cyclic

this compound has a ________ amine and is therefore more __________ (sedative or stimulatory) since it has a higher affinity to ___________ reuptake transporters

secondary, stimulatory, NE

TCA compounds need to somewhat mimic the neurotransmitter in order to fit into their spot

the 2 added aromatic rings __________ binding to the receptor

stabilize

TCA compounds need to somewhat mimic the neurotransmitter in order to fit into their spot

the 2 added aromatic rings stabilize binding to the receptor

the drug’s ___________ effect at the reuptake receptor needs to be strong enough to repeatedly beat out binding of the neurotransmitter

antagonistic

TCA chemistry: the chloride of this compound is able to form a ________ bond with the tertiary amino group, which locks it in place (stops it from freely rotating around); enhances potency and stability of the cis confirmation

hydrogen (H-bond)

TCA chemistry: the chloride of this compound is able to form a H-bond with the tertiary amino group, which locks it in place (stops it from freely rotating around); enhances _________ and __________ of the cis confirmation

potency and stability

TCA chemistry: this compound is sometimes described as “tetra”cyclic

it is chemically accurate, but it' still behaves as a typical TCA

the advantage of this compound that no other TCAs possess is that it has NO _____________ effects🙂

…but its kinda weak and mild lol

why aren’t TCAS anti-psychotic?

due to the skewed ring confirmation and the _________ bridge

ethylene

TCAs structure-activity relationships

position 3: a halogen or cyano at this position enhances activity for _________ reuptake transporters

serotonin (5-HT)

TCAs structure-activity relationships

position 3: a halogen or cyano at this position _________ activity for serotonin reuptake transporters (SERT)

enhances (increases)

TCAs structure-activity relationships

position 3: a halogen or cyano at this position enhances activity for serotonin reuptake transporters (SERT)

example: ____________ which has chlorine at position 3 an forms H-bond with the amino group to stabilize

Clomipramine

TCAs structure-activity relationships

if the free amino group is _________, it has affinity to SERT

tertiary

TCAs structure-activity relationships

if the free amino group is _________, it has affinity to NET

secondary

TCAs structure-activity relationships

the carbonyl chain ideally has 3x carbons

CH3 branching __________ affinity of both SERT and NET; this enhances the sedative-hypnotic effect ☹

decreases

TCAs structure-activity relationships

the carbonyl chain ideally has 3x carbons

CH3 branching decreased affinity of both SERT and NET; this ___________ the sedative-hypnotic effect

increases🤧

TCAs structure-activity relationships

the carbonyl chain ideally has 3x carbons

CH3 branching decreased affinity of both SERT and NET; this increases __________ side-effects

sedative🤧

TCA side effects are due to its non-selective binding to other receptors

like __________ receptor which causes the bothersome anticholinergic effects

muscarinic

TCA anticholinergic effects

1x __________ ______ is essential for binding to the muscarinic receptor

aromatic ring (needs >1 ==> a 2nd ring means even more anticholinergic effects)

TCA metabolic pathways

they are extensively metabolized via combinations of the following three paths

- side chain N-____________

- ring hydroxylation at C2, followed by glucuronidation and ring hydroxylation at C10, followed by glucuronidation

OR

- epoxide formation of the C10,11 double bind

demethylation (more methyl we remove= less and less effective ==> only need to remove 2 from secondary amines; will have to remove 3 from tertiary amines)

TCA metabolic pathways

they are extensively metabolized via combinations of the following three paths

- side chain N-demathylation

- ring ____________ at C2, followed by glucuronidation and ring __________ at C10, followed by glucuronidation

OR

- epoxide formation of the C10,11 double bind

hydroxylation

TCA metabolic pathways

they are extensively metabolized via combinations of the following three paths

- side chain N-demethylation

- ring hydroxylation at C2, followed by ____________ and ring hydroxylation at C10, followed by ___________

OR

- epoxide formation of the C10,11 double bind

glucuronidation

TCA metabolic pathways

they are extensively metabolized via combinations of the following three paths

- side chain N-demethylation

- ring hydroxylation at C2, followed by glucuronidation and ring hydroxylation at C10, followed by glucuronidation

OR

- __________ formation of the C10,11 double bind

epoxide

SSRIs only affect __________ reuptake transporters

serotonin (5-HT)

SSRIs only affect serotonin (5-HT) reuptake transporters

this class has much less side effects than TCAs🙂

one rare SE is _________ __________= increased HR, insomnia, sexual SEs, vomiting, and diarrhea

serotonin syndrome

SSRIs only affect serotonin (5-HT) reuptake transporters

this class has much less side effects than TCAs🙂

this class can have __________ symptoms d/t temporary deficiency in synaptic serotonin= HA, N/V, and agitation

withdrawal (SSRIs must be tapered down)

chemistry of SSRIs

their structure looks very similar to TCAs, but they are missing the ________

center ring

chemistry of SSRIs

highlighted in green, the ______-__________ (=5-HT, NE, and DA) structure is prevalent

aryl-monoamine

chemistry of SSRIs

highlighted in red, an additional aromatic structure enhances binding and ___________ to serotonin

competitiveness

NARIs only affect __________ reuptake transporters

NE

chemistry of NARIs

highlighted in green, the ______-__________ (=5-HT, NE, and DA) structure is prevalent

aryl-monoamine

selective monoamine reuptake inhibitors (SSRIs & NARIs)

substitution in the 2’ position of the ring exhibits selectively and with high affinity for the __________ (5-HT or NE) reuptake transporter, and are therefore generally classified as _________ (SSRIs or NARIs)

NE, NARIs

selective monoamine reuptake inhibitors (SSRIs & NARIs)

substitution in the 4’ position of the ring exhibits selectively and with high affinity for the __________ (5-HT or NE) reuptake transporter, and are therefore generally classified as _________ (SSRIs or NARIs)

5-HT, SSRIs

selective monoamine reuptake inhibitors (SSRIs & NARIs)

substitution in position ___ of the ring exhibits selectively and with high affinity for the serotonin reuptake transporter, and are therefore generally classified as SSRIs

4

selective monoamine reuptake inhibitors (SSRIs & NARIs)

substitution in position ___ of the ring exhibits selectively and with high affinity for the NE reuptake transporter, and are therefore generally classified as NARIs

2

selective monoamine reuptake inhibitors (SSRIs & NARIs)

substitution in position 2’ of the ring exhibits selectively and with high affinity for the NE reuptake transporter, and are therefore generally classified as NARIs

these compounds do not contain halogens and are therefore ______ polar

less

selective monoamine reuptake inhibitors (SSRIs & NARIs)

substitution in position 4’ of the ring exhibits selectively and with high affinity for the serotonin reuptake transporter, and are therefore generally classified as SSRIs

these compounds contain halogens and are therefore ______ polar

more

what class is this compound?

SSRI (substitution at position 4’ (start counting clockwise at oxygen connection) =higher affinity for serotonin)

what class is this compound?

SSRI (substitution at position 4’ (start counting clockwise at oxygen connection) =higher affinity for serotonin)

what class is this compound?

NARI (substitution at position 2’ (start counting clockwise at oxygen connection) =higher affinity for NE)

what class is this compound?

SSRI (substitution at position 4’ (start counting clockwise at wedge connection) =higher affinity for serotonin)

what class is this compound?

SSRI (substitution at position 4’ (start counting clockwise at oxygen connection) =higher affinity for serotonin)

what class is this compound?

SSRI (substitution at position 4’ (start counting clockwise at wedge connection) =higher affinity for serotonin)

what class is this compound?

SSRI (substitution at position 4’ (start counting clockwise at wedge connection) =higher affinity for serotonin)

what class is this compound?

NARI (substitution at position 2’ (start counting clockwise at oxygen connection) =higher affinity for NE)

which of the compounds selectively inhibits the re-uptake of NE?

A (substitution at position 2’ =higher affinity for NE =NARI)

selective 5-HT/NE reuptake inhibitors (SNRIs)

effective on specific types of each neurotransmitter

they are like _______ (class) if they were awesome and more restrictive and had fewer SEs💋

TCAs