Antidepressants

Question 1

What enzyme(s) is/are responsible for TCA metabolism?

Answer 1

CYP 2D6 (major) and 2C19 (minor)

Question 2

Imipramine metabolism

Answer 2

N-demethylation to Desipramine (active)

Question 3

Amitriptyline key point

Answer 3

Highest antimuscarinic and sedative SE’s of TCA’s.

Question 4

Amitriptyline metabolism

Answer 4

N-demethylation to Nortriptyline (active)

Question 5

Nortriptyline key point

Answer 5

Less antimuscarinic and sedative SE’s than Amitriptyline.

Question 6

Doxepin isomeric ratio

Answer 6

85% “E” isomer, 15% “Z” isomer

“Z” isomer is more active however.

Question 7

Doxepin metabolism

Answer 7

N-demethylation to N-desmethyldoxepin (inactive)

Question 8

Doxepin cousins

Answer 8

Zonalon - 5% Doxepin cream: Topical antihistamine.

Silenor - Sleep aid: CNS antihistamine.

Question 9

Maprotiline key point(s)

Answer 9

Tetracyclic ring structure.
- Added rigidity: NET > SERT, 500x

Secondary amine.
- Low sedation and antimuscarinic SE’s

Question 10

Tranylcypromine mechanism

Answer 10

Irreversible inhibition of MAO A and B.

Question 11

Phenelzine mechanism

Answer 11

Irreversible inhibition of MAO A and B.

Question 12

Isocarboxazid key point

Answer 12

Prodrug.

“Amide” hydrolysis yields Benzylhydrazine (active) metabolite

Question 13

Isocarboxazid mechanism

Answer 13

Irreversible inhibition of MAO A and B

- as Benzylhydrazine

Question 14

Selegiline key point(s)

Answer 14

MAO-B-I

Transdermal patch for Parkinson’s Disease

Question 15

Fluoxetine key point(s)

Answer 15

"No" antimuscarinic or sedative SE's
Long t1/2
Metabolite is active: Norfluoxetine
Fluoxetine/Norfluoxetine = 2D6 and 2C19 Inhibitors
30x selective for SERT over NET

Question 16

Fluoxetine metabolism

Answer 16

N-demethylation to Norfluoxetine (active)

Question 17

Sertraline key points

Answer 17

1S,4R-Enantiomer
1400x selective SERT > NET
Moderate 2C19 inhibition
Weak 2D6 inhibition
N-desmethylsertraline metabolite is active

Question 18

Sertraline metabolism

Answer 18

N-demethylation to N-desmethylsertraline (active)

Question 19

Paroxetine key point(s)

Answer 19

3S,4R-Enantiomer
300x selective SERT > NET
*Potent irreversible 2D6 inhibitor
- 2D6 acts on Paroxetine, reactive intermediate, alkylation of enzyme

Question 20

Paroxetine metabolism

Answer 20

2D6 removal of “methylene” to form catechol metabolite (inactive)

Question 21

Fluvoxamine key point(s)

Answer 21

Can be isomerized by UV light (inactive)
Extensive metabolism (inactive)
600x selective SERT > NET
*Potent 1A2 and 2C19 inhibitor

Question 22

Citalopram key point(s)

Answer 22

Most potent SSRI: >300x selective
Racemic mixture
- “S” isomer = Escitalopram
*Weakest P450 inhibitor of all SSRI’s

Question 23

Citalopram / Escitalopram metabolism

Answer 23

N-dealkylation to N-desmethylcitalopram (weakly active)

Question 24

Trazodone key point(s)

Answer 24

Lacks antimuscarinic effects
mCPP metabolite contributes to overall effects
- 5HT2c partial agonist

Question 25

Trazodone metabolism

Answer 25

3A4 cleaves mCPP (active) from alkyl chain and remainder (active)

Question 26

Nefazodone key point(s)

Answer 26

Yields two active metabolites Nefazodone and alpha-hydroxy metabolite are both 3A4 inhibitors. mCPP metabolite contributes to overall effects - 5HT2c partial agonist *Possible hepatic failure / hepatotoxicity

Question 27

Nefazodone metabolism

Answer 27

3A4 cleaves Nefazodone into alpha-hydroxy metabolite (active) and mCPP metabolite (active)

Question 28

Vilazodone metabolism

Answer 28

3A4 dealkylation (inactive)

Question 29

Vortioxetine metabolism

Answer 29

2D6 converts N-methyl to CO2- (inactive)

Question 30

Venlafaxine key point(s)

Answer 30

"No" affinity for M1, H1, or alpha1 receptors | Two metabolism pathways yield two active products

Question 31

Venlafaxine metabolism

Answer 31

3A4 N-demethylation to N-desmethyl metabolite (weakly active) 2D6 O-demethylation to O-desmethyl metabolite: Desvenlafaxine (separate SNRI; active)

Question 32

Desvenlafaxine metabolism

Answer 32

Major - Glucuronidation | Minor - 3A4 N-demethylation

Question 33

Duloxetine key point

Answer 33

Moderate 2D6 inhibition | Significant interaction with Fluvoxamine

Question 34

Duloxetine metabolism

Answer 34

1A2 / 2D6 Naphthyl ring hydroxylation Glucuronidation (inactive)

Question 35

Levomilnacipran key point

Answer 35

1S,2R-Enantiomer

Question 36

Levomilnacipran metabolism

Answer 36

3A4 N-deETHYLation

Question 37

Bupropion key point(s)

Answer 37

``` Amphetamine core structure Restlessness and Insomnia SE's No antimuscarinic or sedative SE's Has active metabolite *Bupropion and metabolite are 2D6 inhibitors ```

Question 38

Bupropion metabolism

Answer 38

*2B6* hydroxylation of methyl group

Question 39

Mirtazepine key point(s)

Answer 39

Tetracyclic ring structure - Basic N-bearing ring attached to 2-atom bridge - Basic N closer to tri-cyclic ring system * No antimuscarinic effects

Question 40

SSRI P450 Inhibitors

Answer 40

Fluoxetine/Norfluoxetine - 2D6 and 2C19 Sertraline - 2C19 (moderate) 2D6 (weak) *Paroxetine - 2D6 (potent and irreversible) *Fluvoxamine - 1A2 / 2C19 (potent and irreversible)

Question 41

"Multimodal" SSRI P450 Inhibitor(s)

Answer 41

Nefazodone and alpha-hydroxy metabolite - 3A4

Question 42

SNRI P450 Inhibitor

Answer 42

Duloxetine - 2D6

Question 43

Atypical P450 Inhibitor

Answer 43

Bupropion and active metabolite - 2D6