Antidepressants Pharmacology - Krouse PART 1

Learning Objectives

• Classify antidepressants

• Explain MOA of medications used to treat depression

• Recognize class effects, contraindications, and drug-specific adverse effects of antidepressants

• compare and contrast the pharmacokinetics of antidepressants and impact

• Recognize which agents are isomers or active metabolites of other antidepressant agents

• Identify critical food and drug interactions

What are the general therapeutic targets by antidepressant hypothesis?

Monoamine hypothesis

• Dopamine

• Serotonin

• Norepinephrine

Newer Drug Targets

• Glutamate

What are the serotonin side effects at each receptor for antidepressants?

5HT3 — nausea (think Zofran)

5HT2a — insomnia

5HT1a — improve sexual dysfunction

5HT2a AND 5HT3 — causes sexual dysfunction

NE side effects — Blood pressure

What components of human affect/mood/neurotransmission is affected by Norepinephrine (NE)?

Alertness, concentration, Energy

What components of human affect/mood/neurotransmission is affected by Dopamine (DA)?

Pleasure, reward, motivation

What components of human affect/mood/neurotransmission is affected by Serotonin (5-HT)?

Obsessions/compulsions, Memory, wake promoting

What components of human affect/mood/neurotransmission is affected by Serotonin (5-HT) AND Norepinephrine (NE)?

Anxiety, Impulse, irritability

What components of human affect/mood/neurotransmission is affected by Dopamine (DA) AND Norepinephrine (NE)?

Attention

What components of human affect/mood/neurotransmission is affected by Dopamine (DA) AND Serotonin (5HT)?

Cognition, Sex, Appetite, Aggression

What components of human affect/mood/neurotransmission is affected by all three neurotransmitters?

MOOD

Points about SSRIs

1. FIRST LINE agents for MDD, many anxiety disorders, PTSD, and OCD

2. PROZAC frist one to be invented

SSRIs work on this synaptic neuron

Presynaptic neuron (work at the SERT)

Post synaptic Serotonin receptors

5Ht1a

5HT2A

• Autoreceptor

• Agonist activity causes insomnia

• Antagonist can cause sedation

• Sexual dysfunction

The only SSRI that is not used for depression, anxiety, panic, etc

Fluvoxamine (OCD only)

What are the SSRIs effect on serotonin?

They increase it by blocking SERT

Which SSRI has the most indications for use? (OCD, MDD, GAD, Panic, PTSD, Hot flashes)

Paroxetine

What SSRI is the most:
1. Activating // Has most diarrhea // Most sedating and anticholinergic // Cause QTc prolongation ?

1. Fluoxetine (activating)

2. Sertraline (diarrhea)

3. Paroxetine (More sedating/anticholinergic)

4. Citalopram (QTc prolong)

SSRIs benefits

• Low lethality in overdose

• No HYPOTENSION

• Less cardiac conduction concerns (except citalopram)

• Less anticholinergic (except paroxetine)

SSRIs adverse effects

Mild weight gain

Sedation

Moderate GI/NV

Moderate insomnia/agitation

Bleeding risk

Withdrawal reactions (taper)

Moderate sexual dysfunction

Brain Zaps with

What electrolyte should we monitor with SIADH (Syndrome of inappropriate ADH secretion) pertaining to SSRIs

Sodium

What should be avoided or used in caution with SSRIs?

DOACs, NSAIDs, Warfarin - bleeding risk

What are the only TWO SSRIs that can be used to treat pediatric depression?

Fluoxetine (Prozac) - ages 8+ (Has the longest had life)

Escitalopram (Lexapro) - 12+

What two SSRIs are potent CYP2D6 inhibitors? and which have active metabolites?

Fluoxetine and Paroxetine (2D6)

Prozac // Sertraline // Celexa // Lexapro

Short Acting SSRIs, Most common, Long acting SSRIs

Short acting:

• Paroxetine

• Fluvoxamine

Common

• Citalopram

• Escitalopram

• Sertraline

Long acting

• Fluoxetine

Citlaopram vs Excitalopram

citalopram only for MDD (20-40mg)

Escitalopram for MDD and GAD (10-20 mg)

S enantiomer is safer

R is riskier

What is DESvenlafaxine in relation to Venlafaxine?

DESvenlafaxine is the metabolite of venlafaxine

What is levomilnacipran in relation to milnacipran?

Levomilnacipran is the L-ISOMER

Venlafaxine points

• SNRI

• for MDD, GAD, SAD, Panic DO

• T1/2 of 5-10hrs

Duloxetine points

• SNRI

• for MDD, GAD, Diabetic Peripheral neuropathy, fibromyalgia, chronic MSK pain

• T1/2 of 12hrs

Desvenlafaxine points

• SNRI

• only for MDD

• T1/2 of 10-11 hrs

Unique Adverse effects of all SNRIs

ALL have Dose dependent HYPERTENSION

• Duloxetine only — increased LFTS and more anticholinergic effects

How is Venlafaxine converted into Desvenlafaxine

Primarily metabolized via CYP2D6 - Active metabolite is O-desmethylvenlafaxine

These TCAs primarily inhibit SERT >> NET

CIAD ——— TERTIARY AMINES

C - Clomipramine

I - Imipramine

A - Amitriptyline

D - Doxepin

These TCAs primarily inhibit/prefer NET > SERT

SECONDARY AMINEs

• Desipramine

• Nortriptyline

• Amoxapine

• Protriptyline

• Maprotiline

BETTER TOLERATED THAN TERTIARY AMINES

TCA Uses - on and off label

• MDD

• Neuropain

• Bed wetting

• Migraine

• OCD

• Panic DO

• GAD

• Sleep

• Anxiety

• Fibromyalgia

• ADHD

Off target effects of TCA’s?

Anticholinergic

Antihistamine

Alpha 1 ANTAGONIST

What is the active metabolite of the tertiary TCA Amitriptyline ?

Nortriptyline!!!

What is the active metabolite of the tertiary TCA Imipramine ?

Desipramine!!!!

What are contraindications of use with TCAs and MAOis?

Do not use TCAs within 14 days of an MAOI!!!

TCAs adverse effects and toxicity

• Minimal insomnia/agitation

• Mild to severe HYPOtension

• Mild to moderate antocholinergic effects

• Minimal GI effects

• Mild sexual dysfunction

• Moderate weight gain

• conduction delays - low to moderate

• LETHAL IN OVERDOSE

Points about TCA use and when to use them

used RARELY for depression and Anxiety!!!!

• classified by chemical structure

• Ideal patient for TCA in depression?

  • Non-impulsive patient you trust

  • worked for them in past

  • Comorbid neuropathy or migraine

  • Comorbid IBS or nocturnal enuresis

Who should TCAs be cautioned for?

Patients with:

• high risk for overdose

• impulsive patients

• patients with borderline personality disorder

• Seizure disorder

• Heart conditions

• Older adults

Steps of TCA overdose

1. Overdose

2. Sodium channel blockade - wide QRS and QT prolong

3. Cardiac conduction interruption/arrhythmias

4. Cardiac arrest