Antidepressants Medchem Flashcards
Dibenzapine (common TCA ring system)
Dibenzocycloheptenes (common TCA ring system)
Dibenzoxepin (common TCA ring system)
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
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
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
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
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
Phenelzine (Nardil) - phenylethylhydrazine/MAOI
Metabolism by MAO to reactive radical followed by irreversibly MAO modification
Isocarboxazid (Marplan)
Beleived to be a prodrug - amide hydrolysis to release active drug
Metabolized to benzylhydrazine which then inactivates MAO
Selegiline (Emsam)
MAO-B inhibitor used to treat Parkinson’s
Delivered as a transdermal patch
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
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
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)
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
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
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
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
Vilazodone (Viibryd) - multimodal SSRI
T1/2 = 25 hours
CYP3A4 dealkylation to inactive metabolites
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
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)
Desvenlafaxine (Pristiq)
O-desmethylvenlafaxine (active SNRI)
T1/2 = 11 hours
Metabolism major route is glucuronidation
Minor route is 3A4 demethylation
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
Levomilnacipran (Fetzima)
No EWG
Single 1S,2R - enantiomer
T1/2=12 hours
Major metabolism is 3A4 mediated N-demethylation
Not a P450 inhibitor
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
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
Clomipramine (3-chloro group)
50x more potent than imipramine; more selective for inhibiting 5HT reuptake
