Anti Depressants

Developed from phenothiazine anti-psychotic agents

Tricyclic antidepressants (TCA’s)

replacement of the sulfur with a ethylene group gave a compound that lost the _______ ______ activity but became an inhibitor of ___ and ___ reuptake

Replacement of the sulfur with a ethylene group gave a compound that lost the Dopamine

antagonist activity but became an inhibitor of 5HT and NE reuptake

Cl substitution as in clomipramine has what effect on 5HT and NE reuptake

Enhances effect 5HT over NE reuptake

Reducing the double bond in the TCAs resulted in

Increased potency as a reuptake inhibitor and yielded imipramine

Side effects of TCA’s

Anticholinergic

Sedation

Hypotension

Cardiotoxicity

First SSRI

Zimeldine

what group on the antidepressants is important for SSRI activity?

Para electron withdrawing group

Para to the oxygen, EDG/EWG is located located on the ring

The ortho substitution EWG or EDG gives compounds with

NERI (Norepinephrine Reuptake Inhibitor) activity (Atomoxetine)

Fluoxetine Use *not tested

Major depression, OCD, Premenstrual Dysphoric Disorder, Panic Disorder with and without agoraphobia

Fluoxetine metabolize

Metabolized by 2C8/9 and 2D6

Inhibitor of both

T/F: Fluoxetine is metabolized by 2C8/9 and 2D6 and is an inducer of both

FALSE

Fluoxetine is metabolized by 2C8/9 and 2D6 and is an inhibitor of both

Fluoxetine ADR

Insomnia, drowsiness, Nausea, diarrhea, anorexia, dry mouth, weakness and Yawning

Fluoxetine is converted to ________ which is active and has a 10 day half-life. + How often do you take it

Converted to norfluoxetine which is active and has a 10 day half-life. This is the rational of Prozac once weekly, the metabolite accumulates over time

Fluvoxamine different from fluoxetine

No second aromatic ring and primary amine

fluvoxamine metabolized

1A2 and 2D6

Inhibits 1A2

Citalopram metabolized

2C19 and 3A4

Citalopram ADR

ADR: drowsiness, insomnia, nausea, dry mouth, Sweating

Escitalopram relationship to citalopram

Escitalopram is the S isomer and is the active form of citalopram

Escitalopram metabolizes

active desmethyl with a long half life (59h)

ADR same as citalopram

Paroxetine unique SSRI

Most potent of the SSRIs

Paroxetine is Potent

Paroxetine metabolized by

2d6

This will accumulate in poor 2d6 metabolizers

sertraline is structurally similar to

chlorpheniramine

sertraline metabolized by

2c19, 2d6, moderate inhibitor of 3a5. 2c19, 2d6

Which of the following are mixed reuptake inhibitors

Escitalopram 

Paroxetine

Duloxetine

Sertraline

Venlafaxine

Venlafaxine and Duloxetine are Mixed

The rest are SSRIs

venlafaxine use

Use Depression, GAD, Social anxiety, Panic disorder

Unlabeled: OCD, Hot flashes, Neuropathic pain, ADHD

venlafaxine metabolized

2D6 and 3A4

Active metabolite O-desmethyl (desvenlafaxine, Pristiq)

active metabolite of venlfacine

desvenlafacine

Duloxetine use

Use: depression, GAD, diabetic neuropathy, chronic pain, management of Fibromyalgia Unlabeled Stress incontinence

duloxetine metabolized

Metabolized by 1A2 2D6, inhibits 2D6

milnacipran active isomer

+ (positive) isomer is active, used in a racemic mixture

milnacipran type

Selective 5-HT and NE reuptake inhibitor

Milnacipran use

Fibromyalgia only

milnacipran metabolism

CP450 metabolism and NOT an inhibitor of CP450, some glucuronide formation, excreted renally

+ (positive) isomer has a longer half-life than the - (negative) isomer

levomilnacipran moa

selective 5-ht and ne reuptake inhibitor

levomilnacipran use

major depression only

levomilnacipran metabolized

3A4 and hydroxylation and glucuronidation

levomilnacipran adr

Nausea and tachycardia (low incidence), small weight loss

levomilnacipran dosage forms

extended release formulation (beads in capsule)

vilazodone moa

New class 5HT reuptake pump and 5HT1A partial agonist (5HT modulator and stimulator)

vilazodone metabolized

3a4 major

2c19 and 2d6 minor (not inhibitor or inducer)

what increases vilazodone levels

3a4 inhibitors increase plasma levels of vilazone

vortioxetine moa

inhibits 5HT reuptake and agonist/partial agonist at 5HT1A also %HT3 antagonist

vortioxetine metabolized

2D6 (primarily)

3A4, 2C19, and others, glucuronidation

Poor metabolizers have 2x plasma levels

vortioxetine metabolite

carboxylic acid metabolite major

vortioxetine adr

Increase QT and nausea

ortho substitution causes switch from fluoxetine to:

atomoxetine

atomoxetine moa

NERI

atomoxetine use

ADHD

atomoxetine metabolism

2D6 to 4-OH which is equal active and desmethyl which is weakly active

Bupropion moa

DA reuptake inhibitor, metabolite is an NE reuptake inhibitor

Bupropion use

Depression and smoking cessation: Unlabeled ADHD

Bupropion metabolized

2B6 hydroxy bupropion and hydrobupropion

bupropion adr

ADR: insomnia, nausea, dry mouth, Sore throat? Seizure

>300 mg/ day non SR or XL formulation

Trazodone moa

atypical antidepressant

weakt 5ht reuptake inhibition, parent and metabolite m-chlorophenyl piperazine are agonists at 5HT1

atypical antidepressant related to trazodone

nefazodone

What MOI are non-selective

Phenelzine

Tranylcypromine

Phenelzine moa

Hydrazine type MAO inhibitor

non-selective for mao (a and B)

tranylcypromine moa

non-selective for MAO (a and B)

tranylcypromine parnate major side effect

chance of hypertensive crisis caused by other MAO Substrates

Selegiline moa

Selective MAO-B

• Only in the brain not the periphery

Selegiline is available in

a once daily transdermal patch for depression

Phenelzine metabolized to

Metabolized by MAO to phenylacetaldehyde → Phenylacetic acid

what drug has an oxidation step that forms a reactive intermediate that can attack functional groups within the enzyme?

Phenelzine

Phenelzine is what type of inhibitor

hydrazine type MAO inhibitor

Phenelzine is converted to

phenylacetic acid

Tranylcypromine metabolized

Cyclopropane derivative once oxidized can react with group within MAO and inactivate

phenelzine major adr

hypertensive crisis caused by other MAO substrates

tranylcypromine major ADR

hypertensive crisis caused by other MAO substrates

Toxic effects for all MAOA inhibitors

Hypertensive crisis is the most serious

Avoid tyramine rich foods as they can increase blood pressure due to no presence of MAO

• most dangerous foods are aged cheese and yeast products

Can interact with sympathomimetic amines in cold preparations like

• ephedrine, phenylpropanolamine, pseudoephedrine, and phenylephrine