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

• Long N. SSRI Toxicity. LITFL
• Nickson C. Serotonin Syndrome. LITFL

References

• Katzung BG. Basic and Clinical Pharmacology. 14e. 2018: 536-549