Central Sympatholytic Drugs

Central sympatholytic drugs reduce sympathetic outflow from the brainstem, lowering peripheral resistance, heart rate and blood pressure. They are later-line antihypertensives and have wider uses in pregnancy hypertension, attention deficit hyperactivity disorder, withdrawal states and sedation.

Members. Alpha-2 agonists: clonidine, guanfacine, methyldopa (through its metabolite), dexmedetomidine and lofexidine. Imidazoline receptor agonists: moxonidine and rilmenidine. Monoamine depleter: reserpine.

Mechanism. Alpha-2A stimulation in the nucleus tractus solitarius and rostral ventrolateral medulla lowers sympathetic tone. Moxonidine and rilmenidine act mainly at I1 imidazoline receptors, with fewer sedative effects. Methyldopa is converted to alpha-methylnoradrenaline, a false transmitter that stimulates central alpha-2 receptors. Reserpine blocks vesicular monoamine uptake and depletes noradrenaline, dopamine and serotonin.

Haemodynamics. Blood pressure falls through lower resistance and modest falls in heart rate and output. Renal blood flow and glomerular filtration are usually preserved. Fluid retention can follow.

Pharmacokinetics. Clonidine is well absorbed with a half-life of 12 to 16 hours and about half is cleared by the kidney. Methyldopa is absorbed variably and acts for 12 to 24 hours. Moxonidine has a half-life of about 2 to 3 hours and is renally cleared. Reserpine acts for days to weeks because of irreversible vesicle binding.

• Clonidine: oral and transdermal; hypertension, opioid and alcohol withdrawal symptoms, attention deficit hyperactivity disorder, menopausal flushing, epidural analgesia and sedation. Rebound hypertension on abrupt stopping.
• Methyldopa: the long-established oral drug for hypertension in pregnancy. Sedation, depression, haemolytic anaemia and hepatitis limit use outside pregnancy.
• Moxonidine: oral; fewer sedative and dry mouth effects than clonidine; contraindicated in heart failure.
• Guanfacine: extended release for attention deficit hyperactivity disorder; immediate release for hypertension.
• Reserpine: low-dose oral antihypertensive; depression and peptic ulcer risk; used as a low-cost add-on in some low-income settings, with limited modern outcome data.
• Dexmedetomidine, lofexidine: intravenous sedation and opioid withdrawal respectively.

• Hypertension in pregnancy: methyldopa 250 mg orally 2 to 3 times daily, increased to a maximum of 3 g daily. Switch to another agent within 2 days after delivery because of the risk of postnatal depression.
• Resistant hypertension: clonidine 50 to 100 micrograms twice or 3 times daily, or a weekly patch of 100 to 300 micrograms/24 hours, added after diuretic, renin-angiotensin blocker, calcium channel blocker and spironolactone. Moxonidine 200 micrograms each morning, increased to 400 micrograms (maximum 600 micrograms daily in divided doses).
• Opioid withdrawal: clonidine 0.1 mg every 6 to 8 hours as tolerated, or lofexidine as licensed.
• Attention deficit hyperactivity disorder: guanfacine extended release 1 mg daily, increased weekly by 1 mg to a weight-based maximum, usually 4 to 7 mg daily.
• Diagnostic use: clonidine 300 micrograms orally with plasma normetanephrine measured after 3 hours helps to separate phaeochromocytoma from other causes of raised catecholamines.
• Selection: use after first-line agents have failed, except methyldopa in pregnancy.

Contraindications. Severe bradycardia, sick sinus syndrome, second or third degree atrioventricular block, severe arrhythmia, heart failure (moxonidine), active liver disease (methyldopa), depression history (methyldopa and reserpine), phaeochromocytoma (methyldopa), and peptic ulcer (reserpine).

Adverse effects. Sedation, dry mouth, constipation, bradycardia, postural hypotension, depression, sexual dysfunction and fluid retention. Methyldopa: haemolytic anaemia with positive direct Coombs test, hepatitis, drug fever, lupus-like syndrome and positive antinuclear antibody. Reserpine: nasal congestion, depression, gastric acid increase.

Withdrawal. Abrupt clonidine withdrawal causes rebound hypertension, tachycardia, headache, sweating and anxiety within 18 to 72 hours, worse with a concurrent beta blocker. Taper over 2 to 4 days or longer. If both drugs are to stop, withdraw the beta blocker first. Treat severe rebound by restarting clonidine, or with phentolamine or labetalol.

Interactions. Tricyclic antidepressants and mirtazapine blunt the effect. Beta blockers worsen rebound. Opioids, benzodiazepines and alcohol add sedation. Monoamine oxidase inhibitors interact with methyldopa and reserpine. Lithium toxicity with methyldopa.

Monitoring. Blood pressure supine and standing, heart rate, sedation and mood, liver tests and blood count with methyldopa, and renal function for moxonidine and clonidine.

Special groups. Pregnancy: methyldopa is established, clonidine has limited data. Breastfeeding: methyldopa is compatible, clonidine can cause infant sedation. Renal impairment: reduce doses and avoid moxonidine with creatinine clearance under 30 mL/min. Older adults: sedation and falls, so start low.