Alpha-2 Agonists


Questions

How do alpha-2 agonists reduce blood pressure?

Norepinephrine activates the alpha-2 adrenergic receptor in the brain, which serves as a negative feedback mechanism to suppress the sympathetic nervous system. Drugs with alpha-2 agonist activity mimic this effect centrally, resulting in suppression of peripheral norepinephrine release and subsequently lowering blood pressure.

As a result, efficacy of these drugs is reflected by the suppression of circulating norepinephrine. This effect is also used in the clonidine-suppression test to establish autonomous catecholamine secretion by pheochromocytomas, which do not suppress catecholamine secretion in response to clonidine.

Which medications act primarily as alpha-2 agonists?

Clonidine, guanfacine, and methyldopa are the most commonly used alpha-2 agonists for the management of hypertension ( Table 38.1 ). Guanfacine is also used in the treatment of attention deficit/hyperactivity disorder. In addition, several medications used for other indications act primarily at the alpha-2 receptor including dexmedetomidine, which is commonly used for sedation in intensive care units ( Table 38.2 ). Lofexidine is approved for treatment of opioid withdrawal.

Table 38.1
Dosing of Commonly Used Alpha-2 Agonists
Dosage Adjustment for Impaired:
MEDICATION TYPICAL DOSE RANGE KIDNEY FUNCTION LIVER FUNCTION CONSIDERATIONS
Clonidine 0.1–0.3 mg three times daily Reduce dose and/or frequency None Half-life ∼12 hours
Prolonged half-life in renal failure
Guanfacine 1–4 mg once daily None Use with caution
CYP3A4 substrate
Half-life ∼17 hours
Methyldopa 250–1000 mg two to three times daily Reduce dose and/or frequency None Rare autoimmune reactions (+ANA, hemolytic anemia) and abnormal liver tests
Active metabolites are renally cleared
Moxonidine 0.2–0.6 mg once daily Reduce dose and/or frequency None Available outside the United States
Contraindicated in heart failure
Prolonged half-life in renal failure
Tizanidine 4–32 mg every 4–6 hours Reduce dose and/or frequency Contraindicated Markedly increased during CYP1A2 inhibitors
ANA, Antinuclear antibody.

Table 38.2
Medications with Alpha-2 Agonist Effects
MEDICATION NOTES
Apraclonidine eye drops For glaucoma
Brimonidine eye drops For glaucoma
Clonidine Most commonly used for hypertension
Dexmedetomidine Used primarily for sedation
Guanfacine Approved for attention deficit/hyperactivity disorder; long half-life
Guanabenz
Lofexidine Approved for opioid withdrawal
Methyldopa Historically used in pregnancy
Moxonidine Available outside of the United States
An imidazoline receptor antagonist
Tizanidine Used as nonopioid pain relief
Xyalazine Veterinary tranquilizer; reported contaminant in street drugs (fentanyl)

When prescribing an alpha-2 agonist, what are the usual doses?

  • See Table 38.2 for usual doses of the most commonly used alpha-2 agonists.

  • Note that, in most cases, the minimal dosing period is 12 hours.

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