α2-Adrenergic Receptor Agonists, α1-Adrenergic Receptor Antagonists: Clonidine, Guanfacine, Minipress and Yohimbine

α₂-Adrenergic Receptor Agonists, α₁-Adrenergic Receptor Antagonists: Clonidine, Guanfacine, Minipress and Yohimbine

For a more detailed discussion of this topic, see α₂-Adrenergic Receptor Agonists, Sec. 31.4, p. 3004 in Comprehensive Textbook of Psychiatry, 9th Edition.

Clonidine was developed initially as an antihypertensive medication because of its noradrenergic effects. It is an α₂-adrenergic receptor agonist and reduces plasma norepinephrine. It has been studied in many neurologic and psychiatric conditions, including attention-deficit/hyperactivity disorder (ADHD), tic disorders, opiates and alcohol withdrawal, and posttraumatic stress disorder (PTSD). Its use has been somewhat limited by sedation and hypotension, which are common, and in children, its use is limited by its cardiac effects. Guanfacine (Tenex), another α₂-adrenergic receptor agonist, has been preferentially used because of its differential affinity for certain α₂-adrenergic receptor subtypes, resulting in less sedation and hypotension. However, there have been fewer clinical studies of guanfacine than of clonidine.

Prazosin (Minipress), an α adrenergic receptor antagonist, has shown benefits in treating sleep disorders associated with post-traumatic stress disorder (PTSD).

Clonidine and Guanfacine

Pharmacologic Actions

Clonidine and guanfacine are well absorbed from the gastrointestinal tract and reach peak plasma levels 1 to 3 hours after oral administration. The half-life of clonidine is 6 to 20 hours and that of guanfacine is 10 to 30 hours.

The agonist effects of clonidine and guanfacine on presynaptic α₂-adrenergic receptors in the sympathetic nuclei of the brain result in a decrease in the amount of norepinephrine released from the presynaptic nerve terminals. This serves generally to reset the body’s sympathetic tome at a lower level and decrease arousal.

Therapeutic Indications

There is considerably more experience in clinical psychiatry with clonidine than with guanfacine. There is recent interest in the use of guanfacine for the same indications that respond to clonidine centers of guanfacine’s longer half-life and relative lack of sedative effects.

Withdrawal from Opioids, Alcohol, Benzodiazepines, or Nicotine

Clonidine and guanfacine are effective in reducing the autonomic symptoms of rapid opioid
withdrawal (e.g., hypertension, tachycardia, dilated pupils, sweating, lacrimination, and rhinorrhea) but not the associated subjective sensations. Clonidine administration (0.1 to 0.2 mg two to four times a day) is initiated before detoxification and is then tapered off over 1 to 2 weeks (Table 2-1).

Table 2-1 Oral Clonidine Protocols for Opioid Detoxification

Clonidine 0.1–0.2 mg PO 4 times a day; hold for systolic BP <90 mm Hg or bradycardia; stabilize for 2–3 days, then taper over 5–10 days OR Clonidine 0.1–0.2 mg PO q4–6h as needed for withdrawal signs or symptoms; stabilize for 2–3 days, then taper over 5–10 days OR Test dose with clonidine 0.1–0.2 mg PO or SL (for patients weighing over 200 lb); check BP after 1 h. If diastolic BP >70 mm Hg and no symptoms of hypotension, begin treatment as follows:
Weight (lb)	Number of Clonidine Patches
<110	1 patch
110–160	2 patches
160–200	2 patches
>200	2 patches
OR Test dose of oral clonidine 0.1 mg; check BP after 1 h (if systolic BP <90 mm Hg, do not give patch) Place two TTS-2 clonidine patches (or three patches if patient weighs >150 lb) on hairless area of upper body; then For first 23 h after patch application, give oral clonidine 0.2 mg q6h; then For next 24 h, give oral clonidine 0.1 mg q6h Change patches weekly After 2 weeks of two patches, switch to one patch (or two patches if patient weighs >150 lb) After 1 week of one patch, discontinue patches
BP, blood pressure; PO, oral; q, every; SL, sublingual; TTS, through the skin. From American Society of Addiction Medicine. Detoxification: Principle and Protocols. In: The Principles Update Series: Topics in Addiction Medicine, section 11. American Society of Addiction, 1997, with permission.

Clonidine and guanfacine can reduce symptoms of alcohol and benzodiazepine withdrawal, including anxiety, diarrhea, and tachycardia. Clonidine and guanfacine can reduce craving, anxiety, and the irritability symptoms of nicotine withdrawal. The transdermal patch formulation of clonidine is associated with better long-term compliance for purposes of detoxification than is the tablet formulation.

Tourette’s Disorder

Clonidine and guanfacine are effective drugs for the treatment of Tourette’s disorder. Most clinicians begin treatment for Tourette’s disorder with the standard dopamine receptor antagonists haloperidol (Haldol) and pimozide (Orap) and the serotonin–dopamine antagonists risperidone (Risperdal) and olanzapine (Zyprexa). However, if concerned about the adverse effects of these drugs, the clinician may begin treatment with clonidine or guanfacine. The starting dose of clonidine for children is 0.05 mg a day; it can be increased to 0.3 mg a day in divided doses. Three months are needed before the beneficial effects of clonidine can be seen in patients with Tourette’s disorder. The response rate has been reported to be up to 70%.

Other Tic Disorders

Clonidine and guanfacine reduce the frequency and severity of tics in persons with tic disorder with or without comorbid ADHD.

Hyperactivity and Aggression in Children

Clonidine and guanfacine can be useful alternatives for the treatment of ADHD. They are used in place of sympathomimetics and antidepressants, which may produce paradoxical worsening of hyperactivity in some children with mental retardation, aggression, or features on the spectrum of autism. Clonidine and guanfacine can improve mood, reduce activity level, and improve social adaptation. Some impaired children may respond favorably to clonidine, but others may simply become sedated. The starting dosage is 0.05 mg a day; it can be raised to 0.3 mg a day in divided doses. The efficacy of clonidine and guanfacine for control of hyperactivity and aggression often diminishes over several months of use.

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