Psychopharmacology and Clinical Application of Guanfacine and Clonidine for ADHD – What’s the Difference?

Posted on:March 20, 2022

Last Updated: December 20, 2022

Time to read: 5 minutes

Psychostimulants are first-line treatments for ADHD. However, some patients may be resistant to treatment or may not tolerate stimulants.

One of the pharmacological treatments for ADHD is the use of guanfacine and clonidine, two α2-adrenoreceptor agonists that have been clinically shown to be effective in managing both the core symptoms and associated comorbidities of the disorder.

Guanfacine and clonidine can be valuable as monotherapy or augmentation agents in ADHD.

Both clonidine and guanfacine stimulate Alpha-2 adrenergic receptors pre and post-synaptically.

While both are effective in treating ADHD, there are notable differences between them in terms of both pharmacological properties and clinical applications.

In this article, we’ll explore what makes guanfacine and clonidine different, and how their respective uses in the treatment of ADHD can lead to better outcomes for those affected by the disorder.

ALPHA-2 RECEPTORS IN ADHD

Neurobiology of Attention Deficit Hyperactivity Disorder (ADHD) – A Primer

Diagnosis and Management of Attention Deficit Hyperactivity Disorder (ADHD) – Focus on Adult ADHD

Noradrenaline / Norepinephrine plays a vital role in the pathogenesis of ADHD. We covered this in more detail in the article on the Neurobiology of ADHD.

Noradrenaline (NA) is an important neurotransmitter that, along with dopamine, regulates Prefrontal Cortex (PFC) cognitive functions. Deficits in PFC function are associated with several features of ADHD.

Three families of adrenergic receptors mediate NA’s effects: α1, α2 and β.

The Cellular Actions of Noradrenaline (NA): [Arnsten, 2009]

At moderate levels, noradrenaline can improve prefrontal cortex functioning by stimulating postsynaptic α2A receptors
NA activation of the α2A receptor strengthens the neuronal signal and hence strengthens network connectivity
Higher levels of NA can impair prefrontal cortex function by stimulating α1 receptors

Thus, DA and NE have complementary beneficial actions, with NA increasing the signal and DA reducing noise, and an optimal balance of both neurotransmitters is required for proper PFC functioning.

Alpha-2 (α2) agonists :

The α2 agonists clonidine and guanfacine mimic norepinephrine (NE) actions in the PFC through the stimulation of postsynaptic α2 A receptors on PFC neurons

MECHANISM OF ACTION OF CLONIDINE | PHARMACOKINETICS | DOSING

Clonidine was initially developed as a hypertensive agent. [Cinnamon Bidwell et al., 2010].

Presynaptic stimulation of alpha-2 (α-2) receptors reduces the firing of noradrenaline (NA) presynaptic neurons, that release NA into the prefrontal cortex, which improves the impulsive and hyperactive behaviour seen in attention-deficit/hyperactivity disorder.
Adjunctive effects on serotonin and γ-aminobutyric acid receptors also assist in treating insomnia in children with attention-deficit/hyperactivity disorder.
Clonidine stimulates postsynaptic α-2 adrenergic receptors and increases noradrenaline signalling to normal levels.
Clonidine also binds the imidazoline receptors contributing to the hypotensive effect.

Dosing:

100-400 mcg /day.
The FDA approved the extended-release version (KAPVAY) for monotherapy or adjunctive treatment at doses of 100 mcg – 400mcg /day. (Children aged 6-17)
An initial dose of 100mcg tablet at bedtime
Daily dosage adjusted in increments of 100mcg/day at weekly intervals.
Administered BD (similar to immediate-release). If the dosage is split, give the higher split dosage at bedtime
Maximum dose 400 mcg/day.

Pharmacokinetics: [FDA PI]

Duration of action of IR – 6-12 hrs.
Duration of action for XR – 24 hrs.

Side Effects:

The most common side effects were somnolence, fatigue, bradycardia, and hypotension.
Heart rate and blood pressure should be measured before initiation of therapy, following dose increases, and periodically while on treatment. Clonidine should be used with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease because it can decrease blood pressure and heart rate.

MECHANISM OF ACTION OF GUANFACINE | PHARMACOKINETICS | DOSING

Guanfacine modified release (INTUNIV) is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents 6-17 years old, as monotherapy (when stimulants or atomoxetine are not suitable, not tolerated or be ineffective) or as adjunctive therapy to psychostimulants (where there has been a sub-optimal response to psychostimulants).

Guanfacine

Mechanism of action:

Guanfacine is a selective α2A-adrenergic receptor agonist with 15-20 times higher affinity for α2A than for the α2B or α2C subtypes and exhibits therapeutic efficacy with a reduced side effect profile compared to clonidine, enhancing prefrontal cortical functioning leading to behavioural improvement.
The recommended starting dose for guanfacine is 1 mg once a day.
Maximum dose 4 mg/day (6-12 years); 7 mg/day (13-17 years) as BD or TDS.
For adjunctive treatment with stimulants maximum recommended dose is 4 mg/day.
Duration of action: 24 hours
Discontinuation should be gradual to avoid rebound hypertension.

Guanfacine Modified Release (MR) (Intuniv): [PI]

Dosing

The initial dose is 1 mg oral for both monotherapy and when co-administered with psychostimulants.
The dose is adjusted in increments of no more than 1 mg/week for both monotherapy and when co-administered with psychostimulants.
The recommended maintenance dose range depending on clinical response and tolerability for Guanfacine MR is 0.05-0.12 mg/kg/day to balance the exposure-related potential benefits and risks. Doses above 4 mg /day are not recommended.
Guanfacine MR has shown both short term and long-term benefits in treating ADHD.

Pharmacokinetics:

Side Effects:

The most common side effects were somnolence, fatigue, bradycardia, and hypotension.
Heart rate and blood pressure should be measured before initiation of therapy, following dose increases, and periodically while on treatment. Clonidine should be used with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease because it can decrease blood pressure and heart rate.

CLONIDINE VS GUANFACINE - WHAT IS THE DIFFERENCE

Clonidine is 10 times more potent than guanfacine at α-2 presynaptic receptors, while guanfacine appears more potent at postsynaptic receptors. Activity at postsynaptic alpha-2 receptors translates to enhanced prefrontal cortical regulation of attention and impulse control by strengthening PFC functions. [Strange, 2008]
Furthermore, guanfacine’s selectivity to the α2A-adrenergic receptor agonist with 15-20 times higher affinity for α2A than for the α2B or α2C subtypes results in therapeutic efficacy with a reduced side effect profile compared to clonidine, enhancing prefrontal cortical functioning leading to behavioural improvement.
Clonidine also binds to the imidazoline receptors, potentiating the hypotensive effect more than guanfacine.
The TGA approves Guanfacine MR in Australia for the treatment of ADHD in children and adolescents (6-17)
Guanfacine modified-release can be administered once daily.
In Australia, clonidine is not approved for the treatment of ADHD; however, clinically, it is used to manage specific comorbidities in ADHD such as tics [ Joo & Kim, 2018] or insomnia [Nguyen et al, 2014].