Mechanism of Action of Viloxazine
Viloxazine acts primarily as a selective norepinephrine reuptake inhibitor (NRI) with additional significant serotonergic modulating properties, making it best classified as a serotonin norepinephrine modulating agent (SNMA). 1
Primary Mechanisms
- Inhibits the reuptake of norepinephrine by binding to and inhibiting the norepinephrine transporter (Ki=0.13 μM) 2
- Demonstrates significant serotonergic activity through:
- Increases extracellular serotonin levels in the prefrontal cortex, a brain area implicated in ADHD 1
Pharmacodynamic Properties
- Viloxazine's dual action on both noradrenergic and serotonergic systems distinguishes it from pure norepinephrine reuptake inhibitors 1
- The serotonin modulating activity is considered an important (possibly predominant) component of its mechanism of action, complemented by moderate norepinephrine transporter inhibition 1
- At therapeutic doses, viloxazine achieves high receptor occupancy at its target receptors 1
Pharmacokinetic Properties
- Viloxazine demonstrates linear pharmacokinetics with dose-proportional increases in Cmax and AUC over dosage ranges from 100 mg to 600 mg once daily 2
- Steady-state is reached after two days of once-daily administration with no accumulation observed 2
- The mean half-life of viloxazine is approximately 7.02 ± 4.74 hours 2
- Primarily metabolized by CYP2D6, UGT1A9, and UGT2B15 enzyme systems 2
- Renal excretion is the primary route of elimination, with 90% of the dose recovered in urine within 24 hours post-dose 2
Historical Context
- Viloxazine was originally developed and used as an antidepressant in Europe for approximately 30 years before being withdrawn from European markets in 2002 3, 4
- It has been repurposed in an extended-release formulation for the treatment of attention-deficit/hyperactivity disorder (ADHD) 4
- Compared to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine demonstrated a relatively low risk for cardiotoxicity 4
Differentiation from Other ADHD Medications
- Unlike pure NRIs such as atomoxetine, viloxazine's mechanism involves significant serotonergic modulation 1, 5
- Unlike stimulants, viloxazine has a decreased potential for substance abuse and dependence 5
- Viloxazine elevates dopamine levels in the nucleus accumbens considerably less than traditional stimulant ADHD treatments 5
- Its unique pharmacological profile as an SNMA provides a different option in the non-stimulant treatment arsenal for ADHD 3, 1
This dual mechanism of norepinephrine reuptake inhibition combined with serotonergic modulation explains viloxazine's therapeutic effects and differentiates it from other medications used in the treatment of ADHD.