Pharm 101: Fluoxetine

Class

Selective serotonin reuptake inhibitor (SSRI)


Pharmacodynamics of SSRIs
  • Allosterically inhibit serotonin transporter (SERT) by binding the SERT receptor at a site other than the serotonin binding site
    • 80% of transporter activity is inhibited at therapeutic doses
  • Effects:
    • Acute increase of serotonergic synapse activity
    • Slower changes in several signalling pathways and neurotrophic activity
  • Other effects:
    • Tonic inhibition of dopamine system
    • No effect on norepinephrine transporter (NET)
    • No binding to histamine or muscarinic receptors

Pharmacokinetics of fluoxetine
  • In general, SSRIs are highly protein bound, have a large volume of distribution, and a long plasma half-life
  • Bioavailability 70%
  • Highly lipophilic
  • Protein binding 95%
  • Large volume of distribution 2500L
  • Plasma half-life 48-72 hours
  • Metabolised to active product, norfluoxetine (half-life 180 hours)
    • Fluoxetine must therefore be discontinued for 3 weeks before an MAOI can be administered to reduce risk of serotonin syndrome
  • CYP2D6 inhibitor

Clinical uses of SSRIs
  • Depression
  • Anxiety disorders
  • OCD
  • PTSD
  • Premenstrual Dysphoric Disorder (PMDD)

Adverse effects of SSRIs
  • Predictable from potent inhibition of SERT
  • Gastrointestinal upset:
    • Nausea, diarrhoea, abdominal discomfort
    • Usually on initiation and improve after first week
    • Due to increased serotonergic activity in gut
  • Sexual dysfunction:
    • Loss of libido, delayed orgasm, diminished arousal
    • 30-40% prevalence
    • Often persist with treatment
    • Due to increased serotonergic tone at level of spinal cord
  • Headaches
  • Sleep disturbances (insomnia or hypersomnia)
  • Discontinuation syndrome:
    • Seen with cessation of short half-life SSRIs such as paroxetine and sertraline
    • Dizziness, paraesthesiaes and other symptoms 1-2 days after cessation, continuing for one week or longer

Precautions/contraindications
  • Combination of SSRI with a MAOI may precipitate serotonin syndrome
  • Fluoxetine is a potent CYP2D6 inhibitor, and co-administration of 2D6 substrates such as TCAs can cause TCA toxicity

Further reading

References

Pharm 101 700

Pharmacology 101

Top 200 drugs

MBBS (UWA) CCPU (RCE, Biliary, DVT, E-FAST, AAA) Emergency Medicine Advanced Trainee in Melbourne, Australia. Special interests in diagnostic and procedural ultrasound, medical education, and ECG interpretation. Editor-in-chief of the LITFL ECG Library. Twitter: @rob_buttner

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