From the Guidelines
Clonidine and guanfacine are pharmacologically very similar, and their main mechanism of action is an agonistic effect at alpha-2 adrenergic receptors throughout the brain, leading to enhanced noradrenergic neurotransmission in the prefrontal cortex, which improves attention and impulse control. The mechanism of action of these two medications involves binding to alpha-2 receptors in the brain stem, which reduces sympathetic outflow from the central nervous system, resulting in decreased blood pressure, heart rate, and peripheral vascular resistance 1.
Key Points
- Clonidine and guanfacine are centrally-acting alpha-2 adrenergic receptor agonists that work primarily in the brain stem and prefrontal cortex.
- They enhance norepinephrine signaling through alpha-2A receptors, which improves attention and impulse control, explaining their utility in ADHD treatment.
- Guanfacine is more selective for alpha-2A receptors, which may contribute to its slightly different side effect profile and longer duration of action compared to clonidine.
- The sedative effects commonly experienced with these medications result from their actions on alpha-2 receptors in the locus coeruleus, which regulates arousal and sleep-wake cycles.
- Clonidine and guanfacine differ regarding their potency, with guanfacine being approximately ten times less potent than clonidine, and also differ in respect to metabolization, with clonidine being primarily metabolized via CYP2D6 and guanfacine being primarily metabolized via CYP3A4 1.
Mechanism of Action
The mechanism of action of clonidine and guanfacine can be broken down into several key steps:
- Binding to alpha-2 receptors in the brain stem, which reduces sympathetic outflow from the central nervous system.
- Reduction in peripheral vascular resistance and consequently lower blood pressure.
- Enhancement of norepinephrine signaling through alpha-2A receptors in the prefrontal cortex, which improves attention and impulse control.
- Actions on alpha-2 receptors in the locus coeruleus, which regulates arousal and sleep-wake cycles, resulting in sedative effects. While they share the same primary mechanism, the differences in potency, selectivity, and metabolization between clonidine and guanfacine may contribute to their slightly different side effect profiles and durations of action 1.
From the FDA Drug Label
CLINICAL PHARMACOLOGY Clonidine stimulates alpha-adrenoreceptors in the brain stem. CLINICAL PHARMACOLOGY Guanfacine Tablets, USP are an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of central α 2-adrenergic receptors.
The mechanism of action of both clonidine and guanfacine is the stimulation of alpha-adrenoreceptors in the brain stem, which results in a decrease in peripheral vascular resistance and a reduction in heart rate 2 3.
- Clonidine stimulates alpha-adrenoreceptors, reducing sympathetic outflow from the central nervous system, which leads to decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure.
- Guanfacine stimulates central α 2-adrenergic receptors, reducing sympathetic nerve impulses from the vasomotor center to the heart and blood vessels, resulting in a decrease in peripheral vascular resistance and a reduction in heart rate.
From the Research
Mechanism of Action of Clonidine and Guanfacine
- Clonidine and guanfacine are alpha-2 adrenergic agonists that have been used to treat various conditions, including attention-deficit hyperactivity disorder (ADHD), hypertension, and substance abuse 4.
- The mechanism of action of clonidine involves binding to the three subtypes of alpha-2 receptors (A, B, and C), which reduces the firing of noradrenaline neurons in the locus ceruleus, leading to a decrease in arousal 4.
- Guanfacine, on the other hand, binds more selectively to alpha-2A receptors, which enhances prefrontal function 4.
- The activation of alpha-2 adrenergic receptors by clonidine and guanfacine leads to a decrease in the release of noradrenaline, which in turn reduces the symptoms of ADHD, such as inattention, hyperactivity, and impulsivity 5, 6, 7.
- The alpha-2 adrenergic agonists also have a role in the control of wakefulness, blood pressure, and antinociception, and their pharmacology has been elucidated through investigations into the molecular pharmacology of alpha-2 adrenoceptors 8.
Pharmacological Effects
- Clonidine and guanfacine have been shown to be effective in reducing the symptoms of ADHD, with guanfacine being associated with significant decreases in commission errors and omission errors on the Continuous Performance Test (CPT) 5.
- The most common side effects of clonidine and guanfacine are sedation, fatigue, and somnolence, with reductions in heart rate and blood pressure being modest and rarely leading to discontinuation of treatment 4, 6, 7.
- Guanfacine has been shown to be safe and effective for treating ADHD, with no serious adverse events reported in clinical trials 6.
- The efficacy of alpha-2 agonists, including clonidine and guanfacine, has been demonstrated in monotherapy and add-on trials to stimulant therapy, with significant reductions in overall ADHD symptoms, hyperactivity, and inattention 7.