Antidepressants Medchem Flashcards Preview

Pharmacy School 2016-17 > Antidepressants Medchem > Flashcards

Flashcards in Antidepressants Medchem Deck (27):
1

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Dibenzapine (common TCA ring system)

2

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Dibenzocycloheptenes (common TCA ring system)

3

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Dibenzoxepin (common TCA ring system)

4

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Imipramine (Tofranil) - TCA

T1/2 = 8-16 hours

Tertiary amine group

Undergoes N-demethylation, yielding Desipramine (marketed as separate TCA) -- secondary amine with T1/2 of 7-60 hours

5

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Amitriptyline - TCA

T1/2 = 16-90 hours

Dibenzoheptene - has highest antimuscarinic and sedative side effects of the TCAs

Metabolism by N-demethylation to Nortriptyline (active secondary amine metabolite, less sedating with fewer antimuscarinic effects)

 

**secondary amines aren't as potent at the muscarinic receptor

6

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Doxepin - TCA

T1/2 = 15 hours

Dibenzoxepine (z isomer most active but delivered as 85% E, 15% Z isomer)

Metabolism to N-desmethyldoxepin (T1/2 = 30 hours)

Zonalon - 5% Doxepin cream for rashes and itching

Silenor - used as a sleep aid

7

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Maprotiline - TCA

Bicyclic central ring increases rigidity beyond that of typical TCAs (actually a tetracyclic)

More selective for inhibiting NE over 5HT transporter (500 fold)

Could be due to secondary amine or rigidity

Reduced sedation and antimuscarinic effects relative to other TCAs (due mainly to secondary amine)

Metabolism by N-demethylation, causing loss of most affinity

8

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Tranylcypromine (Parnate) - trans-2-phenylcyclopropylamine/MAOI

Cyclized amphetamine (phenylethylamine core)

Irreversible inhibitor of MAO

Lack selectivity for MAO A and B

Metabolism to radical cation and then to radical intermediate whcih can irreversibly modify the MAO active site through covalent modification

9

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Phenelzine (Nardil) - phenylethylhydrazine/MAOI

Metabolism by MAO to reactive radical followed by irreversibly MAO modification

10

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Isocarboxazid (Marplan)

Beleived to be a prodrug - amide hydrolysis to release active drug

Metabolized to benzylhydrazine which then inactivates MAO

11

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Selegiline (Emsam)

MAO-B inhibitor used to treat Parkinson's

Delivered as a transdermal patch

12

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Fluoxetine (Prozac) - SSRI

T1/2 = 1-3 days for acute dosing; 4-6 days chronic

F3C electron withdrawing group great for activity and selectivity

No antimuscarinic and sedative side-effects

30-fold selective for blocking SERT over NET

Metabolism: N-dealkylation on secondary amine to Norfluoxetine (primary amine) which also acts as an SSRI with a T1/2 of 4-16 days

 

Prozac Weekly formulation delivered as 90mg DR cap - takes advantage of very long T1/2 for fluoxetine and norfluoxetine

*both are CYP2D6 inhibitors with potential for drug interactions

 

Wait 2 weeks after use of MAOI therapy to start fluoxetine. Wait 5 weeks after fluoxetine therapy has stopped to start MAOI therapy. DUe to long elimination half lives of fluoxetine and norfluoxetine

13

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Sertraline (Zoloft) - SSRI

Electron withdrawing Chlorine groups | secondary amine

Used as single 1S,4S-enantiomer

1400-fold more selective for inhibiting SERT over NET

T1/2 = 24 hours

N-desmethylsertraline (T1/2 = 62-104 hours) - less active SSRI

Sertraline is a weak 2D6 inhibitor and a moderate 2C19 inhibitor

14

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Paroxetine (Paxil)

EWG Fluorine group | secondary amine

Used as single 3S,4R enantiomer (300-fold more selective for SERT over NET)

Potent irreversible inhibitor of 2D6 through formation of reactive intermediate which alkylates the enzmye (removal of methylene --> formation of inactive catcechol)

15

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Fluvoxamine (Luvox) - SSRI

F3C EWG | oxime group | primary amine

T1/2 = 14-15 hours

600-fold more selective for inhibiting SERT

Chemically can be isomerized by UV light to inactive Z-isomer

Extensive metabolism but NO active metabolites
Potent inhibitor of CYP1A2 and 2C19

16

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Citalopram (Celexa)/Escitalopram (Lexapro)

EWG cyano group and EWG Flourine | tertiary amine

Citalopram delivered as racemic mixture (S active)

Most selective of the SSRIs (3000-fold)

T1/2 = 36 hours (metabolized to desmethylcitalopram - active bust less than parent)

Weakest P450 inhibitor of all SSRIs, making it a great option when looking at potential drug interactions

17

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Trazodone - Multimodal SSRI

T1/2 = 6 hours

EWG Cl group

Lacks antimuscarinic effects

CYP3A4 metabolism to m-chlorophenylpiperazine (mCPP)

mCPP is a 5HT2c partial agonist which may contribute to antidepressant effects

18

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Nefazodone - multimodal SSRI
T1/2 = 2-4 hours

3A4 metabolism to mCPP (T1/2 = 4-9 hours) or to alpha-hydroxymetabolite (active with T1/2 1.5-4 hours)

Possible hepatic failure/hepatotoxicity

 

Nafazodone + a-hydroxymetabolite are both 3A4 inhibitors

19

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Vilazodone (Viibryd) - multimodal SSRI

T1/2 = 25 hours

CYP3A4 dealkylation to inactive metabolites

20

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Vortioxetine (Brintellis) - Multimodal SSRI

No EWGs | secondary amine

T1/2 = 66 hours

CYP2D6 metabolism mostly to inactive metabolite

No apparent induction or inibition of P450s

21

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Venlafaxine (Effexor) - SNRI

No affinity for MI, H1 or a1 receptors (unlike TCAs)

No EWGs | tertiary amine

T1/2 = 4-5 hours

Metabolized by 2D6 (O-demethylation) to Desvenlafaxine or through 3A4 to N-desmethyl metabolite (minimal SNRI activity)

22

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Desvenlafaxine (Pristiq)

O-desmethylvenlafaxine (active SNRI)

T1/2 = 11 hours

Metabolism major route is glucuronidation

Minor route is 3A4 demethylation

23

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Duloxetine (Cymbalta) - SNRI
No EWGs on either ring

T1/2 = 12 hours

Structure is similar to fluoxetine

1A2 and 2D6 metabolism = Napthyl ring hydroxylation and glucuronidation (inactive)

Moderate 2D6 inhibition

24

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Levomilnacipran (Fetzima)

No EWG

Single 1S,2R - enantiomer

T1/2=12 hours

Major metabolism is 3A4 mediated N-demethylation

Not a P450 inhibitor

25

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Bupropion (Wellbutrin)

Amphetamine core

T1/2 = 21 hours

Metabolism by hydroxylation by CYP2B6 (active metabolite contributes significantly)

SEs: restlessness, insomnia (due to amphetamine like structure?)

No antimuscarinic or sedative SEs

Bupropion and metabolite are 2D6 inhibitors

26

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Mirtazapine (Remeron)

Tetracyclic moleucle distinct from TCAs

Basic N-containing ring fused to 2-atom bridge | basic N cloaser to tricyclic ring (no antimuscarinic effects)

T1/2 = 20-40 hours

Doesn't inhibit P450s

27

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Clomipramine (3-chloro group)

50x more potent than imipramine; more selective for inhibiting 5HT reuptake