3 Clinical psychopharmacology3.3 Pharmacodynamics

3.3.6.6 Adrenergic agonists

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Written by Resident Doctor Committee · Published

Central alpha-2 agonists

Adrenergic effects depend on receptor and site: central alpha-2 activation lowers sympathetic output, while many peripheral agonists raise it.

  • Clonidine, guanfacine and lofexidine are direct agonists acting mainly at presynaptic alpha-2 autoreceptors, which cuts noradrenaline release and central sympathetic outflow.

  • Presynaptic alpha-2 receptors couple to Gi/o proteins and reduce cyclic AMP, calcium entry and noradrenaline release.

  • Clonidine also activates brainstem imidazoline receptors, lowering heart rate and blood pressure.

Follow the dashed line from the presynaptic alpha-2 autoreceptor to the release site: an agonist such as lofexidine stimulates this receptor and so cuts further noradrenaline release, unlike atomoxetine, which blocks the noradrenaline transporter. Drawn for MRCPsychiatrist

Guanfacine in ADHD

  • Guanfacine treats attention deficit hyperactivity disorder (ADHD) through selective alpha-2A agonism at postsynaptic prefrontal receptors.

  • Stimulants, atomoxetine and bupropion work differently: they raise synaptic catecholamines by blocking reuptake or releasing them.

  • Because guanfacine activates receptors directly, it has low misuse liability and is not a controlled drug.

  • Its UK licence covers ages 6 to 17 when stimulants are unsuitable, ineffective or not tolerated.

Opioid withdrawal

  • Alpha-2 agonists reduce autonomic withdrawal signs such as sweating, tachycardia and lacrimation, and lofexidine causes less hypotension than clonidine.

Adverse effects

  • Somnolence is the most frequent adverse effect of guanfacine and is very common, which sets it apart from the stimulant ADHD drugs.

  • Postural hypotension is very common with clonidine, because central alpha-2 agonism reduces sympathetic outflow.

  • Both drugs also cause bradycardia, dizziness and dry mouth.

  • Abrupt clonidine withdrawal can cause rebound severe hypertension, headache and agitation within 24 to 72 hours, so people should taper under supervision.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.