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Psych/Neuro EXAM 2
Psych/Neuro EXAM 2 Neito Antidepressants
29
Pharmacology
Graduate
08/24/2011

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Term
TCAs - norepinephrine-serotonin reuptake inhibitors
general structural properties
Definition
[image]

all have a tricycle system:
2 aromatic rings and a center 7 member ring
6-7-6 system
the tricycle ring may or may not be substituted

side chain:
all substituted at the same position
all have a tertiary amine 3 carbons away from the tricycle system
Term
TCAs - selective norepinephrine reuptake inhibitors
general structural properties
Definition
[image]

tricyclic system:
2 aromatic rings
6-7-6 system except for maprotiline
tricyclic ring may or may not be substituted

side chain:
SECONDARY AMINE
amoxepine - not linear but is still a secondary amine and is still 3 atoms away from the tricycle AND the side chain is at a different position compared to the others
Term
TCAs SAR
Definition
[image]

tricyclic ring system
SIDE CHAIN:

basic terminal amino groups (3C chain); secondary and tertiary amines

secondary amines are more NE selective
tertiary amines: NET and SERT inhibitors; in vivo there is an N-demethylation that turns them into secondary amines

branching reduces affinity, but will not completely lose affinity

geometry in TCAs is important for selectivity and affinity

ANTIPSYCHOTIC VS. ANTIDEPRESSANT ACTIVITY:

should be able to look at a structure and determine if it is an antipsychotic or an antidepressant


[image]

in the phenothiazines (antipsychotics) the CIS form is more active
having an O in the seven member ring breaks the symmetry; if it is a C, then the molecule is symmetrical (the O draws the N towards it into the correct position)
BLUE is the GOOD antidepressant WITH antipsychotic activity (CIS)
RED is TRANS and is BAD for antipsychotic activity

ring system not related to SERT or NET inhibition; important for dopamine receptors

halogen or cyano group = SERT
[image]
antipsychotic activity = dopamine antagonism
best position for a substitution (for antispychotic activity) = position 2!!!
electron withdrawing groups help with antidepressant effect and antipsychotic effects

CONFORMATION AFFECTS ANTIPSYCHOTIC ACTIVITY
CONFORMATION DOES NOT AFFECT ANTIDEPRESSANT ACTIVITY
[image]
for the antidepressant activity, it is not necessary to have a planar molecule
phenothiazine: closest to planarity = antipsychotic acitivty (dopamine receptor activity)
addition of the brige in dibenzobicyclooctadiene breaks the planarity of the system and makes it a better antidepressant

substituent on position 2:
electron withdrawing groups -> antipsychotic activity

N or sp2C not required for antidepressant activity
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6-6-6 system: no antidepressant activity IF PLANAR
[image]
addition of the bridge breaks the planarity = antidepressant activity
Term
metabolism of TCAs
Definition
common routes:
N-demethylation
aromatic hydroxylation
"bridge" hydroxylation

[image]

all the TCAs that are tertiary amines will have a secondary N-demethylated metabolite that will have antidepressant activity as well

NOR/DES/DESMETHYL prefixes means it has lost 1 methyl group

amitriptyline -> nortriptyline
clomipramine -> desmethylcomipramine
doxepine -_ desmethyldoxepine
imipramine -> desipramine
maprotiline -> desmethylmaprotiline

amoxepine -> 8-OH-amoxepine
desimpramine -> 2-OH-desipramine
nortriptyline -> 10-OH-nortriptyline
Term
ADRs of TCAs
Definition
narrow therapeutic window

overdose: prolongation of QRS and QT interval

side effect associated with binding at many different receptors:
sedation
anticholinergic effects
hypotension
CARDIAC EFFECTS
weight gain
Term
MOA of Venlafaxine

[image]
Definition
non-TCA norepinephrine-serotonin reuptake inhibitor

preferential affinity for SERT (30 times)

O-desmethyl metabolite has the same pharmacological profile (NOT N-desmethyl)

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Term
MOA of duloxetine

[image]
Definition
non-TCA norepinephrine-serotonin reuptake inhibitor

5 times preferential inhibition of SERT

bioisosteric replacement of fluoxetine

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Term
SSRI design
Definition
[image]

losing the bridge between the 2 aromatic rings = open TCA

N in the phenyl ring

tertiary amine 3 carbons away fromt he system

electron withdrawing group (Br)

MORE SELECTIVE towards serotonin reuptake transporters
Term
example SSRIs
Definition
[image]
Term
SSRIs SAR
Definition
phenoxyphenylakylamines
[image]

only the phenoxy group can be substituted
substitutions in the para (4) position = serotinergic selectivity
substitutions in the ortho (2) potition = NE selectivity
di-substitutions = loss of selectivity (but not activity)
[image]

semirigid analogs (paroxetine):
[image]
alkyl chain is a cycle = semirigid
loss of affinity; retention of selectivity for SERT
Term
properties of citalopram
Definition
[image]

phenylspiro-benzofuran nucleus: benzyl-furan is like a phenyl ring (bioisotere)

S-citalopram is the active isomer:
red = chiral center

is the most selective SSRI in the market
Term
properties of paroxetine
Definition
[image]

constrained form (fluoxetine)
semirigid: part of the side chain is in a ring limiting the number of conformations the drug can have

2 chiral centers (red)

the SERT affinity is reduced by:
alkylation of the secondary amine
changes on the position of F
Term
SSRI metabolism
Definition
ACTIVE desmethyl metabolites:
citalopram -> desmethylcitalopram
fluoxetine -> norfluoxetine
sertraline -> desmethylsertraline

venlafaxine -> O-desmethylvenlafaxine
Term
SSRIs ADRs
Definition
relatively safe in overdose

overdose symptoms: nausea, agitation, seizures, loss of consciousness

SSRIs may impair platelet function

relatively NO cardiac ADRs (as compared to TCAs)
Term
properties of the MAO enzyme
Definition
MAO-A
preferred substrates: NE, epinephrine, and serotonin

MAO-B
preferred substrates: tyramine, phenylethylamine, and benzylamine

MAO-A and MAO-B
dopamine and tryptamine
Term
MOA of MAO inhibition
Definition
[image]
Fl = flavin

one electron mechanism:
electron transfer to flavin generating a radical
the radical undergoes rapid cleavage and a double bond is formed
the double bond interacts with the enzyme forming a covalent bond (irreversible) attachment to the cysteine residue
the MAO is COMPLETELY INHIBITED
the only way that MAO can be used again is if it is regenerated
Term
MAO-I properties
Definition
[image]

selectivity: MAO-A vs. MAO-B
MAO-B = selegeline and rasagiline
RIMAs (reversible MAOIs) = moclobemide and brofaromine (not available in the US)

"wash-out" of RIMAs: shorter than other MAO-Is
normally MAO needs a long time to be regenerated (2-4 weeks)
Term
metabolism of meclobemide (MAO-I)
Definition
meclobemide -> lactam

[image]
Term
MAO-Is ADRs
Definition
sleep problems
orthostatic hypotension
GI disturbances
sexual disturbances
overstimulation (anxiety)

NO cardiac effects
Term
MAO-I drug interactions
Definition
food interactions (cheese and wine effect)

tyramine or tryptophan containing food

prescription and non-prescrition drugs
Term
example serotonin receptor modulators
Definition
[image]
Term
MOA of sertonergics
Definition
nefazodone and trazodone are weak inhibitors of SERT and NET

nefazodone and trazodone: high affinity for 5HT-2A (antagonists)

trazodone metabolite: 5HT-2C agonist

5HT-1 and mixed function ligand = partial agonist/antagonist
Term
serotonergics SAR
Definition
[image]

small or no N4 substituent: 5HT-1A affinity

aryl portion can be widely variable
doesn't matter what type, BUT HAS TO BE AROMATIC
can be bicyclic as long as it is AROMATIC

unbranched spacer (2-5 carbons long)

terminus: aromatic or heteroaromatic, imide or amide

bulky region modifies functional activity

PIPERIZINE RING (6 member ring with 2 Ns) is COMMON for all
Term
serotonergics metabolism
Definition
[image]

nucleophile will open the epoxide group and cause hepatotoxicity
Term
serotonergics ADRs
Definition
nefazodone DOES NOT equal trazodone

trazodone:
effects related to the 5HT and alpha1 antagonism (sedation and hypotension)
sexual dysfunction (decreased libido, erectile dysfunction, and anorgasmia)

nefazodone:
safer but potent inhibitor of CYP3A4
does not form an active metabolite
Term
MOA of mirtazepine
[image]
Definition
enhanced central noradrenergic and serotonergic activity

very little affinity for SERT or NET

antagonism of serotonergic receptors = antidepressant activity
Term
metabolism of mirtazepine
[image]
Definition
[image]

N-demethylation
ring hydroxylation
N-oxide
glucuronidation of metabolites
Term
MOA of bupropion
[image]
Definition
DAT inhibitor

used for smoking cessation treatment
Term
metabolism of bupropion

[image]
Definition
[image]

tert-butyl inhibits dealkylation

other metabolites:
hydroxypropion (hydroxylation of the tert-butyl group)
reduction of the aminoketone

ALL THE METABOLITES ARE ACTIVE

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