1. Introduction
Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. One pharmacologic approach involves adrenergic uptake inhibitors, which enhance norepinephrine signaling in the central nervous system (CNS).
These drugs are particularly useful in patients who:
- Do not tolerate stimulants
- Have comorbid anxiety or tics
- Require non-stimulant therapy for ADHD
The most widely used adrenergic uptake inhibitor is atomoxetine.
2. Mechanism of Action
Adrenergic uptake inhibitors selectively inhibit the norepinephrine transporter (NET):
- NET normally reabsorbs norepinephrine (NE) from the synaptic cleft back into presynaptic neurons.
- Inhibition → increased synaptic NE in the prefrontal cortex
- Enhanced NE transmission improves:
- Attention and executive function
- Impulse control
- Working memory
Key difference from stimulants: No significant dopamine increase in the striatum, so lower abuse potential.
3. Common Agents
| Drug | Mechanism | Clinical Notes |
|---|---|---|
| Atomoxetine | Selective norepinephrine reuptake inhibitor (NRI) | FDA-approved non-stimulant for ADHD; once or twice daily dosing; delayed onset (2–4 weeks) |
| Guanfacine ER | α2A-adrenergic receptor agonist (indirect NE modulation) | Adjunct or monotherapy; sedating effects; helps with hyperactivity/tics |
| Clonidine ER | α2-adrenergic receptor agonist | Mainly adjunct for impulsivity and sleep disturbances in ADHD |
Note: While guanfacine and clonidine are α2 agonists rather than classical uptake inhibitors, they modulate adrenergic signaling and are often grouped with non-stimulant ADHD therapies.
4. Pharmacokinetics
Atomoxetine (example):
- Absorption: Rapid oral absorption; peak plasma 1–2 hours
- Metabolism: Liver via CYP2D6
- Half-life: 5–20 hours (dependent on CYP2D6 genotype)
- Excretion: Primarily renal
Clinical Implication: CYP2D6 poor metabolizers may have higher plasma levels → increased side effects.
5. Clinical Indications
- ADHD in Children and Adults
- Inattention-predominant ADHD
- Patients at risk for stimulant misuse
- Adjunct Therapy
- In patients with comorbid anxiety, tic disorders, or insomnia
- For hyperactive/impulsive symptoms when stimulants are inadequate
- Special Populations
- Patients with cardiac risk, where stimulants may be contraindicated
6. Efficacy
- Atomoxetine improves attention, executive function, and overall ADHD rating scales (e.g., ADHD-RS, Conners’ Rating Scale).
- Response may take 2–4 weeks, unlike stimulants, which act rapidly.
- Meta-analyses indicate moderate effect size; less robust than stimulant therapy but clinically significant, especially for non-stimulant-eligible patients.
7. Adverse Effects
Common
- Gastrointestinal: Nausea, vomiting, decreased appetite
- Sleep disturbances: Insomnia or somnolence
- Cardiovascular: Mild increases in heart rate and blood pressure
- Mood changes: Irritability, emotional lability
Rare but Serious
- Suicidal ideation (black box warning in children/adolescents)
- Severe liver injury (rare; monitor LFTs if symptomatic)
- Hypertension or tachyarrhythmias
8. Drug Interactions
- CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) → increase atomoxetine levels
- Antihypertensives may interact with α2 agonists (guanfacine, clonidine) → excessive hypotension or bradycardia
- Stimulants can be combined cautiously; monitor cardiovascular status
9. Dosing Considerations
Atomoxetine (example):
- Initial: 0.5 mg/kg/day
- Maintenance: 1.2 mg/kg/day (max ~100 mg/day)
- Once daily in the morning or divided doses
- Titration based on efficacy and tolerability
α2 agonists (Guanfacine ER, Clonidine ER):
- Start low (1 mg/day) → titrate slowly
- Give evening dose if sedation occurs
10. Monitoring Parameters
- Blood pressure and heart rate at baseline and periodically
- Weight and growth in children
- Liver function if symptomatic (rare hepatotoxicity)
- Monitor for emergent suicidal thoughts
11. Special Considerations
- Pregnancy & breastfeeding: Limited data; use only if benefits outweigh risks
- CYP2D6 polymorphisms: Affect atomoxetine metabolism
- Cardiac conditions: Monitor ECG if history of arrhythmias
- Combination therapy: Can be safely combined with stimulants or behavioral therapy for optimal effect
12. Summary
Adrenergic uptake inhibitors provide a non-stimulant alternative for ADHD therapy by increasing norepinephrine in the prefrontal cortex.
Key Points:
- Atomoxetine is the primary agent; guanfacine and clonidine modulate adrenergic pathways indirectly
- Slower onset (weeks) compared to stimulants
- Effective for attention and impulse control, especially in non-stimulant-eligible patients
- Monitor cardiovascular parameters, growth in children, and mental health
- Safe alternative in patients with substance abuse risk
13. References
- Michelson D, et al. Atomoxetine in the treatment of children and adolescents with ADHD: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2001;40:1204–1211.
- Banaschewski T, et al. Efficacy and safety of guanfacine extended-release in children and adolescents with ADHD. J Child Adolesc Psychopharmacol. 2008;18:527–540.
- Kratochvil CJ, et al. Atomoxetine and cardiovascular safety in children and adolescents with ADHD. Pediatrics. 2005;116:e379–e385.
- Faraone SV, Buitelaar J. Comparing the efficacy of stimulants and non-stimulants in ADHD. J Clin Psychiatry. 2010;71:1423–1434.
- Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th Edition, 2021.
