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 Emergency Medicine Trainee with interests in medical education, ECG interpretation, and the use of point-of-care ultrasound in the undifferentiated patient. Co-author of the LITFL ECG Library | Twitter

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