SN5 SHORT NOTE 5M ★ High-yield

Describe clonidine and methyldopa. Add a note on rebound hypertension.

Pharmacology · 2nd Professional — Para-Clinical

Definition

Centrally acting sympatholytics reduce sympathetic outflow from the brainstem by stimulating alpha2 adrenergic receptors (and imidazoline receptors) in the vasomotor centre.

Clonidine and Methyldopa Compared

Feature	Clonidine	Methyldopa
Nature	Direct partial alpha2 agonist	A prodrug — converted to alpha-methylnoradrenaline, a false transmitter that is itself an alpha2 agonist
Site	Vasomotor centre; reduces central sympathetic outflow	Same, after central conversion
Effect on heart rate	Bradycardia	Little change
Chief adverse effects	Sedation, dry mouth, and severe rebound hypertension on abrupt withdrawal	Sedation, positive COOMBS test with haemolytic anaemia, drug-induced hepatitis, depression, galactorrhoea
Chief use	Resistant hypertension; opioid and nicotine withdrawal; menopausal flushing; as an adjunct in anaesthesia	Hypertension IN pregnancy — the drug of choice, with the longest record of fetal safety

CLINICAL PEARL

Methyldopa survives in practice for one reason only: a very long safety record in pregnancy. It is sedating, causes a positive Coombs test in up to a fifth of patients and occasionally hepatitis — effects that would rule out a new drug. But decades of use have shown no harm to the fetus, and in obstetrics that evidence outweighs a more comfortable but less well-characterised alternative.

Rebound Hypertension

Prolonged alpha2 stimulation suppresses central sympathetic outflow → Peripheral adrenergic receptors UP-regulate in compensation → The drug is stopped abruptly → Sympathetic outflow returns at once, now acting on increased numbers of receptors → Severe rebound hypertension with tachycardia, sweating, headache and anxiety — within 12 to 48 hours

Clonidine must always be tapered, never stopped suddenly; the same principle applies to beta-blockers, and for the same reason
Treated with reinstatement of clonidine, or with phentolamine and labetalol; a beta-blocker alone makes it worse through unopposed alpha stimulation

Other Uses of Clonidine

Opioid, alcohol and nicotine withdrawal — suppresses the autonomic overactivity (sweating, tachycardia, agitation) that dominates the syndrome
Menopausal hot flushes
Attention deficit hyperactivity disorder and Tourette syndrome
Dexmedetomidine, a more selective alpha2 agonist, is widely used for sedation in intensive care because it sedates without depressing respiration
Diagnostic clonidine suppression test in suspected phaeochromocytoma

Applied Aspects

Methyldopa, labetalol and nifedipine are the antihypertensives of choice in pregnancy; ACE inhibitors, ARBs and atenolol are avoided
Check a blood count and liver function periodically on methyldopa, and warn the patient about jaundice and about fatigue from anaemia
A positive Coombs test alone is not a reason to stop methyldopa — only about 1 to 2% develop actual haemolysis; but it will confuse cross-matching, and the blood bank must be told
Warn every patient on clonidine never to run out of tablets, since missing doses is the commonest cause of rebound; this matters where supply is intermittent
Sedation limits daytime use of both drugs, and is the usual reason patients stop them without telling anyone

All questions in Autonomic Nervous System

Every Pharmacology chapter →