Alpha Adrenergic Agonists

Alpha adrenergic agonists activate alpha-1 receptors (vasoconstriction, mydriasis, bladder neck closure) or alpha-2 receptors (reduced sympathetic outflow, sedation, analgesia). Alpha-1 agonists raise blood pressure and relieve congestion, while alpha-2 agonists lower blood pressure, sedate and reduce ocular pressure.

Alpha-1 agonists. Phenylephrine, metaraminol, midodrine (prodrug of desglymidodrine), droxidopa (prodrug of noradrenaline), oxymetazoline, xylometazoline and naphazoline.

Alpha-2 agonists. Clonidine, dexmedetomidine, brimonidine, apraclonidine, methyldopa (prodrug of alpha-methylnoradrenaline), guanfacine, tizanidine and lofexidine. Xylazine, a veterinary alpha-2 agonist, is encountered as an adulterant of street opioids.

Mechanism. Alpha-1 activates Gq with calcium-mediated smooth muscle contraction. Alpha-2 activates Gi, reducing cyclic AMP, and presynaptic stimulation reduces noradrenaline release. Central alpha-2 stimulation in the brainstem lowers sympathetic outflow. Imidazoline receptor effects add to clonidine action.

Haemodynamics. Alpha-1 agonists raise systemic vascular resistance and mean arterial pressure and cause reflex bradycardia, with a fall in cardiac output in poor ventricular function. Alpha-2 agonists reduce blood pressure and heart rate, but intravenous bolus can briefly raise pressure.

Pharmacokinetics. Phenylephrine given intravenously acts for about 10 to 20 minutes. Midodrine is well absorbed, with desglymidodrine acting for 2 to 3 hours. Dexmedetomidine has a half-life of about 2 hours. Clonidine has a half-life of 12 to 16 hours.

• Phenylephrine: pure alpha-1; anaesthesia hypotension, spinal hypotension, eye drops (mydriasis), nasal decongestion.
• Metaraminol: mixed direct and indirect; hypotension under anaesthesia.
• Midodrine: oral for orthostatic hypotension; boxed warning for supine hypertension.
• Droxidopa: oral for neurogenic orthostatic hypotension.
• Oxymetazoline, xylometazoline: topical nasal decongestion; overuse causes rebound congestion.
• Clonidine: oral, transdermal, epidural; hypertension, opioid withdrawal, ADHD, sedation.
• Dexmedetomidine: intravenous sedation without significant respiratory depression.
• Brimonidine: topical for glaucoma and facial erythema in rosacea.
• Apraclonidine: topical for glaucoma and diagnosis of Horner syndrome, where reversal of anisocoria indicates sympathetic denervation supersensitivity.
• Methyldopa: oral for hypertension in pregnancy.

• Hypotension under anaesthesia and neuraxial block: phenylephrine 50 to 100 micrograms intravenously, repeated, or infusion titrated to blood pressure. Preferred over ephedrine at caesarean section because of lower foetal acidosis.
• Neurogenic orthostatic hypotension: midodrine 10 mg orally 3 times daily, last dose at least 4 hours before bedtime and not later than 6 pm. Start 2.5 mg in renal impairment. Droxidopa 100 mg 3 times daily, titrated to a maximum of 600 mg 3 times daily. Keep the head of the bed raised.
• Nasal congestion: oxymetazoline or xylometazoline for no more than 5 to 7 days to avoid rebound rhinitis.
• Hypertension: clonidine 50 to 100 micrograms 2 to 3 times daily; methyldopa 250 mg 2 to 3 times daily to a maximum of 3 g daily, used in pregnancy hypertension.
• Sedation: dexmedetomidine 0.2 to 0.7 micrograms/kg/hour after optional loading.
• Opioid withdrawal: clonidine or lofexidine to reduce autonomic symptoms.
• Hepatorenal syndrome: midodrine 7.5 mg orally 3 times daily, titrated to 12.5 to 15 mg, with octreotide and albumin, if terlipressin is unavailable.
• Selection: use alpha-1 agonists for vasodilatory hypotension without heart failure. Avoid in low output states.

Contraindications. Alpha-1 agonists: severe hypertension, severe ischaemic heart disease, acute renal failure (midodrine), urinary retention, and closed-angle glaucoma. Alpha-2 agonists: bradycardia, heart block and severe depression.

Adverse effects. Alpha-1: hypertension, reflex bradycardia, piloerection, scalp pruritus, urinary retention, and tissue ischaemia on extravasation. Alpha-2: sedation, dry mouth, bradycardia, hypotension, depression and fluid retention. Methyldopa: haemolytic anaemia with positive direct Coombs test, hepatitis and depression.

Clonidine withdrawal. Abrupt cessation causes rebound hypertension, tachycardia and anxiety within 18 to 72 hours, worst with concurrent beta blockers. Taper over 2 to 4 days or longer. If both are to be stopped, withdraw the beta blocker first.

Extravasation. Infiltrate phentolamine 5 to 10 mg in 10 mL of 0.9% sodium chloride.

Interactions. Monoamine oxidase inhibitors, tricyclic antidepressants, ergot alkaloids and oxytocin increase pressor response. Beta blockers worsen clonidine rebound. Atropine blunts reflex bradycardia. Alpha-2 agonists add sedation with opioids, benzodiazepines and alcohol.

Monitoring. Supine and standing blood pressure, heart rate, sedation level, liver function and blood count (methyldopa), and renal function.

Special groups. Pregnancy: methyldopa is established, and phenylephrine is used at caesarean section. Older adults: orthostatic and sedative effects are greater. Children: avoid nasal decongestants in infants. Renal impairment: reduce midodrine and clonidine doses.