Fluoxetine

Mechanism

Chemical and Commercial Profile

Common trade names: Prozac, Adofen, Reneuron.
Group: SSRI antidepressant (propylamine derivative).

Mechanism of Action

It competitively and allosterically inhibits the serotonin transporter (SERT or SLC6A4), blocking the presynaptic reuptake of 5-HT and prolonging its stay in the synaptic cleft. Additionally, it has antagonistic properties at the 5-HT_2C receptors (K_i ≈ 90 nM), which disinhibits the local release of dopamine and norepinephrine in the prefrontal cortex, giving it an early energizing profile.

Pharmacokinetics

Pharmacokinetics

• Routes of administration: Oral (tablets, capsules, solution).
• Absorption: Excellent oral bioavailability (85%). It is not altered by food. Maximum concentration (C_max) at 6-8 hours.
• Metabolism: Hepatic through oxidative demethylation by the isoenzyme CYP2D6, generating the active metabolite with a long half-life norfluoxetine.
• Excretion: Renal (80%) in the form of conjugated metabolites; biliary/fecal (15%).
• Half-life (t_1/2): Fluoxetine: 2-4 days. Norfluoxetine: 7-15 days. It allows flexible dosing and reduces the risk of rebound after missed doses.

Indicators and dose

Indications

• Unipolar Major Depression (MDD).
• Obsessive-Compulsive Disorder (OCD).
• Bulimia Nervosa (approved at high doses to reduce binge eating).
• Panic Disorder and Premenstrual Dysphoric Disorder (PMDD).
• Off-label: Premature ejaculation, trichotillomania, binge eating disorder.

Dosage and Settings

• Adults: MDD, OCD: 20 mg/day orally, increments of 20 mg at weekly intervals to a maximum of 80 mg/day. Bulimia: 60 mg/day.
• Pediatrics (>8 years): 10-20 mg/day.
• Renal Failure: No adjustment required if Cl_Cr 30 ml/min. In end-stage renal disease, space doses or schedule alternate days.
• Liver Failure: Decrease the dose by 50% or space the administration interval due to the extreme prolongation of norfluoxetine.

Security

Contraindications

Absolute

• Concomitant use of MAOIs (wait at least 5 weeks after stopping fluoxetine to start an MAOI).
• Simultaneous use with pimozide or thioridazine (severe risk of QTc interval prolongation).

Relative

• Personal history of mania or hypomania.
• Unstable epilepsy or history of seizures.
• Uncontrolled ischemic heart disease.

Adverse Effects (ADR)

Clinical Interactions

• Enzymatic inhibition: It is a potent inhibitor of CYP2D6 and a moderate inhibitor of CYP2C19. It increases plasma levels of tricyclic antidepressants, beta blockers, and reduces the activation of prodrugs such as tamoxifen.
• Serotonergic substances: Risk of serotonin syndrome in combination with linezolid, tramadol, triptans, St. John's wort and lithium.

Pregnancy and Breastfeeding

FDA Category: C. It is not conclusively associated with major malformations, although some epidemiological records suggest a slight increase in the risk of cardiac septal defects if used in the first trimester. Risk of persistent pulmonary hypertension of the newborn (PPHN) if exposed late in pregnancy. Breastfeeding: Avoid. It passes into breast milk in considerable quantities (Relative Infant Dose ~6-9%), with sertraline or paroxetine being preferred.