Clonidine
Central alpha 2 agonist for hypertension, withdrawal and sedation
Clonidine is a centrally acting α2 adrenoceptor agonist with additional affinity for imidazoline receptors (I1). Boehringer Ingelheim originally developed the substance as a nasal decongestant before its antihypertensive effect was recognised. Trade names include Catapresan and Paracefan, and several generics are available in Germany. Clonidine has been in clinical use since the 1960s and is one of the oldest antihypertensives still in routine practice.
The modern role of clonidine reaches well beyond hypertension. In intensive care it is used for sedation and for treatment of alcohol and opioid withdrawal. In neurology it is used in ADHD, tic disorders and Tourette syndrome. In anaesthesia it serves as premedication and to reduce opioid demand. In paediatrics it is also used off label for sleep disturbances in hyperactive children. The substance is versatile, but by no means harmless: circulatory and rebound phenomena demand attention.
Mechanism of Action
Clonidine acts as an agonist at presynaptic α2 adrenoceptors in the noradrenergic brainstem nuclei, particularly in the locus coeruleus and the rostral ventrolateral medulla. Activation of these autoreceptors inhibits central sympathetic outflow. Peripheral sympathetic tone falls, heart rate and peripheral vascular resistance decrease, and arterial blood pressure drops.
Clonidine also activates I1 imidazoline receptors in the ventrolateral medulla. These receptors mediate a comparable sympatholytic effect, but with less sedation. Newer antihypertensives such as moxonidine preferentially use this pathway.
In the spinal dorsal horn clonidine inhibits the transmission of nociceptive signals. Combined with opioids it produces an additive analgesic effect that reduces opioid requirements in the postoperative and palliative setting. In alcohol and opioid withdrawal the central sympathetic dampening suppresses typical symptoms such as tachycardia, sweating, tremor and agitation. The need for substitution medication is reduced.
Indications
- Arterial hypertension: reserve therapy, in treatment resistant hypertension in combination with other antihypertensives
- Hypertensive emergency: intravenous administration, rapid blood pressure lowering
- Alcohol withdrawal syndrome: reduction of sympathetic symptoms, as adjunct to benzodiazepines
- Opioid withdrawal: relief of autonomic withdrawal symptoms
- Intensive care: sedation and analgosedation, particularly to spare opioids and benzodiazepines
- Attention deficit hyperactivity disorder (ADHD): second choice after methylphenidate and atomoxetine, also in tic disorders
- Tourette syndrome: motor and vocal tics
- Menopausal hot flushes: option when hormone therapy is contraindicated
- Anaesthesia: premedication for anxiolysis and reduction of perioperative catecholamine peaks
Dosage and Administration
Arterial hypertension, oral therapy: start with 75 to 150 µg twice daily, titrate by blood pressure up to a maximum daily dose of 900 µg. Transdermal patches: available in some countries, not routinely approved in Germany. Intravenous: slow application over 10 minutes, usually 75 to 150 µg per dose, carefully titrated because of an initial blood pressure rise.
Alcohol and opioid withdrawal: 75 to 300 µg every 6 to 8 hours, individualised by blood pressure and symptoms. Sedation in intensive care: continuous infusion of 0.5 to 2 µg per kg per hour under close monitoring.
Renal impairment: dose reduction because of renal elimination; halve the starting dose. Hepatic impairment: no formal adjustment, caution in severe dysfunction. Tablets can be taken with or without food.
Side Effects
Very common (over 10 percent): dry mouth, sedation and fatigue, orthostatic hypotension, bradycardia.
Common (1 to 10 percent): dizziness, headache, sleep disturbance, constipation, nausea, weight gain, erectile dysfunction, depression.
Uncommon to rare: AV block, Raynaud phenomenon, rash, pruritus, hallucinations, nightmares, hepatitis, gynaecomastia, Sjögren like complaints (dry eyes).
Important: rebound hypertension upon abrupt discontinuation. Within 24 to 48 hours of stopping, blood pressure can rise sharply, with headache, tachycardia, agitation and, in isolated cases, hypertensive crises. Long term therapy must only be tapered.
Interactions
- Beta blockers: enhanced bradycardia, rebound hypertension on withdrawal is intensified. Beta blockers should be tapered before clonidine
- Tricyclic antidepressants (amitriptyline, imipramine): abolish the antihypertensive effect, rebound hypertension is intensified
- Neuroleptics, benzodiazepines, opioids, alcohol: enhanced central depression, risk of respiratory depression
- Other antihypertensives: additive blood pressure lowering, often intended, monitoring required
- Digitalis glycosides, calcium channel blockers (verapamil, diltiazem): additive bradycardia and AV conduction disturbances
- MAO inhibitors: greater blood pressure fluctuations, combine only with caution
Special Notes
Discontinuation: never stop abruptly. Taper over 7 to 14 days in small steps. If beta blockers are also used, taper those first, then reduce clonidine. Do not interrupt clonidine during anaesthesia; intravenous bridging is possible.
Contraindications: bradycardic arrhythmias (sick sinus syndrome, AV block grade II and III), severe depression, severe bradycardia, hypovolaemia, severe cerebrovascular insufficiency, concomitant therapy with substances that strongly slow AV conduction.
Pregnancy: experience is limited, use is possible on a strict indication, particularly in pre existing hypertension around delivery. Breastfeeding: passage into breast milk occurs, breastfeeding during therapy is not recommended or only under medical supervision.
Monitoring: regular blood pressure and heart rate, continuously during intravenous use and in intensive care. Orthostatic testing in ambulatory older patients. Inform patients about sedative effects, particularly for drivers and machine operators.
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Frequently Asked Questions
Why must I not stop clonidine suddenly?
Clonidine centrally suppresses the sympathetic nervous system. Abrupt discontinuation triggers an exaggerated adrenergic counter regulation. Rises in blood pressure, tachycardia, agitation and hypertensive crises have been described. The drug should be reduced stepwise over one to two weeks.
Does clonidine help in alcohol withdrawal?
Clonidine dampens the autonomic component of alcohol withdrawal, including sweating, tachycardia, rising blood pressure and tremor. It does not replace benzodiazepines, which lower the risk of seizures during withdrawal. A combination under inpatient observation is typical.
Does clonidine cause tiredness?
Yes, fatigue and reduced concentration are among the most common side effects. They are usually most pronounced at the start of therapy and often ease after a few weeks. Driving ability and operation of machinery may be impaired, particularly during the titration phase.
Is clonidine allowed in children?
In paediatrics clonidine is used in ADHD, tic disorders and Tourette syndrome. Use is off label in many European countries; in the United States an extended release paediatric formulation exists. Prescription and titration belong in the hands of child and adolescent psychiatry specialists.
Sources
- EMA, European Medicines Agency
- AWMF, Guidelines on Alcohol Withdrawal and Hypertension
- Gelbe Liste, Clonidine active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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