Pharmacology of Antidepressants

Depression [Major Depressive Disorder] Overview

results from pathological & chronic low serotonin and / or norepinephrine signaling in the brain

Serotonin with Nutrition

low tryptophan dietary intake = less serotonin = express depression in predisposed pts

SSRI [Selective Serotonin Reuptake Inhibitor] MOA

selectively block serotonin transporter [SERT] = block reuptake of serotonin [5-HT]

SSRI Names

Fluoxetine, Paroxetine, Sertraline, Escitalopram

SSRI Initial AE

occurs in hours - days

GI upset, CNS stim, Restlessness ~ imrpove with time

SSRI Delayed Therapeutic response

occurs in 1-6 weeks

gradual improvement of depressive symptoms

SNRI [Serotonin & Norepinephrine Reuptake Inhibitor] Names

Duloxetine, Venlafaxine

SNRI MOA

block SERT = block reuptake of serotonin [5-HT]

SNRI Unique AE

incr BP at high doses

SNRI Clinical Pearl

Shorter DOA compared to SSRI

more discontinuation syndrome

SSRI & SNRI Treatment

Major Depressive Disorder

Anxiety Disorders

Eating Disorders

PMDD [Premenstrual Dysphoric Disorder]

• Fluoxetine, Paroxetine Sertraline

Fibromyalgia, neuropathy, musculoskeletal pain

• Duloxetine

Fluoxetine Indications

Acute & Maintenance Depression

Acute & Maintenance OCD

Acute & Maintenance Bulimia [ED]

Acute Panic Disorder [Anxiety]

PMDD [Periods]

Duloxetine Indications

GAD [Anxiety]

Diabetic Neuropathy

Chronic Musculoskeletal Pain

ADME: SSRI & SNRI

rapid oral absorption

metabolized by CYP3A4 & CYP2D6

• metabolism of SSRI = active metabolites

Kinetics: SSRI & SNRI

long t1/2 [typically 24h]

greater likelihood with shorter t1/2 of toxic responses, least with fluoxetine

shorter act drugs [SNRI] cause more severe discontinuation syndrome [withdrawal]

SSRI AE

CNS stim [insomnia]

Akathisia [motor restlessness]

Weight Gain [typically weight loss]

sexual dysfunction [decr libido]

SSRI / SSRI Toxicity

high therapeutic index, fatalities rare

dangerous in combo with MAO-Inhibitors or Serotonin Enhancers [antidepressants/triptans]

OD Symptoms with SSRI & SNRI

SNRI Overdose

HTN

SSRI/ SNRI DDI

Fluoxetine, Paroxetine, Duloxetine ~~ inhibit CYP2D6

• not good w/ TCA, haloperidol, oxycodone, BB, antiarrythmics

Erythromycin, Ketoconazole, Grapefruit Juice Inhibit CYP3A4

Quinidine, Haloperidol, Clomipramine Inhibit CYP2D6

Few DDI with Sertraline

TCA Names

Amitriptyline [3rd Amine] + Desipramine [2nd Amine]

TCA MOA

block reuptake transporters of both 5-HT & NE [SERT & NET]

block receptors [a1 adrenergic + H1 histamine]

• SE since hit receptors & SSRI / SNRI don’t!!

TCA Initial AE

in hours - days

Drowsiness, dry mouth, constipation, anxiety, dysphoria, difficulty in concentration

TCA Delayed Therapeutic Response

in 1-6 weeks

gradual improvement of depressive symptoms

can also tx Anxiety [OCD, Panic] & Pain [Neuropthic, Migraine]

TCA AE

tachycardia, arrythmias ~ B1 block recep

orthostatic hypotension ~ a1 block recep

anticholinergic

sedation, memory impairment, hallucinations

incr appetite, weight gain [H1 block]

delayed orgasm [a1 block] + decr libido [SERT block]

TCA Overdose Toxicity

Low Therapeutic Index! = dangerous in overdose due to arrythmias