Clonidine

Reviewed and revised 8 February 2025

CLASS

• direct acting, selective alpha-2 adrenergic agonist
• Centrally acting sympatholytic
• imidazoline derivative

MECHANISM OF ACTION

• Receptor Interactions: Clonidine stimulates presynaptic alpha-2a adrenergic receptors in the brainstem (specifically the locus coeruleus) and spinal cord.
  • These receptors have autoinhibitory effects.
  • Some effects may also be mediated by postsynaptic alpha-2 receptors and non-adrenergic imidazoline receptors.
  • α2 > α1 >>>>> β;  α₂:α₁ selectivity ratio 220:1
• Anatomic Locations:
  • Brainstem: Reduces sympathetic outflow
  • Spinal Cord: Modulates pain transmission.
  • Ocular: ciliary body and iris dilator muscle (dilator pupillae)
  • GI tract: enteric neurons and enterocytes
• Second Messenger Pathways: Involves Gi protein-coupled receptors, which inhibit adenylate cyclase, decreasing cAMP levels. This leads to decreased norepinephrine release (especially from peripheral sympathetic nerve endings)
• Pharmacodynamic Effects:
  • CVS:
    • Decreased blood pressure (decreased noradrenaline-mediated alpha1 effect on vascular smooth muscle – possible direct alpha2b-mediated vasodilation in some vascular beds)
    • Decreased heart rate (decreased noradrenaline-mediated alpha1 and beta1 effect on the heart)
  • CNS: Sedation and analgesia
  • Ocular: Decreased production of aqueous humor, increased and miosis
  • GI: decreased fluid secretion, increased fluid absoprtion, prolonged intestinal transit time

PHARMACEUTICS

• Oral Tablets: Immediate-release (0.1 mg, 0.2 mg, 0.3 mg), Extended-release (0.1 mg).
• Transdermal Patch: Delivers 0.1 mg/24 hr, 0.2 mg/24 hr, or 0.3 mg/24 hr.
• Epidural Injection: Used for pain management.
• pKa 8.3

DOSE

• ICU sedation:
  • Starting Rate: 0.5 micrograms/kg/h
  • Usual Rate Range: 0.2 to 2 microgram/kg/h
  • Adjustments: Increase by 0.2 micrograms/kg/h every 1-2 hours as needed, based on the target sedation score and level of delirium/agitation
• Hypertension:
  • Oral: 0.1 mg bd, titrate up to 0.2-0.6 mg/day in divided doses.
  • Transdermal: 0.1 mg/24 hr patch weekly, titrate up to 0.3 mg/24 hr.
• ADHD:
  • Extended-release: 0.1 mg nocte, titrate up to 0.4 mg/day in divided doses.
• Pain Management:
  • Epidural: 30 mcg/h, titrate as needed.

INDICATION

• ICU sedation
• Hypertension (second line agent)
• Attention Deficit Hyperactivity Disorder (ADHD)
• Pain management (epidural)
• Numerous other off-label indications including:
  • withdrawal syndromes (especially opiates, alcohol, and nicotine)
  • menopausal flushing
  • migraine prophylaxis
  • diarrhoea from diabetic autonomic neuropathy
  • atrial fibrillation
  • Tourette syndrome
  • hyperhidrosis
  • posthepatic neuralgia
  • psychosis/ mania
  • originally developed as a nasal decongestant
  • phaeochromocytoma diagnosis (suppression of catecholamine urinary excretion)
  • glaucoma (clonidine derivative apraclonidine is more commonly used)

CONTRA-INDICATIONS

• Hypersensitivity
• Severe bradyarrhythmia: sick sinus syndrome, AV nodal block, severe bradycardia
• Hypotension

Precautions

• Decreased level of consciousness
• Recent myocardial infarction or severe Coronary Insufficiency
• Cardiac failure
• Pheochromocytoma
• Depression
• Autonomic failure (risk of hypertension due to lack of central sympatholytic effect combine with peripheral alpha-2B-medicated vasoconstriction)

DRUG-DRUG INTERACTIONS

• Beta-blockers and Calcium channel blockers (bradycardia and hypotension)
• Tricyclic Antidepressants (TCAs) (decreased antihypertensive effect of clonidine and increase the risk of drowsiness, dry mouth, dizziness, and constipation)
• Antipsychotics, alcohol, and other CNS depressants (sedation)
• MAO Inhibitors (hypertensive crises)

ADVERSE EFFECTS

• Common:
  • CNS: Drowsiness, vivid dreams or nightmares, dizziness, fatigue, miosis
  • Cardiovascular: Hypotension, postural hypotension, bradycardia
  • Gastrointestinal: Dry mouth, constipation
  • sexual dysfunction
  • contact dermatitis from transdermal application
  • SIADH
  • Rebound hypertension (and tachycardia) upon abrupt discontinuation
  • tachyphylaxis (likely due to down-regulation of alpha2 receptors)
• Life-threatening:
  • Severe hypotension
  • Bradycardia and/or AV blockade leading to syncope
  • Anaphylaxis

PHARMACOKINETICS

• Absorption: Rapid oral absorption, bioavailability ~75-95%. Transdermal has 60% bioavailabilty. Peaks at 2h after oral, 12h after transdermal adminstration.
• Distribution: Vd ~2.1 L/kg, crosses blood-brain barrier, 20% protein bound in plasma.
• Metabolism: Hepatic, primarily via CYP2D6.
• Excretion: Renal, 40-60% unchanged; half-life ~12-16 hours. Clearance 3.1 mL/min/kg

PREGNANCY AND LACTATION

• Pregnancy: Category C. Use only if potential benefit justifies the risk.
• Lactation: Excreted in breast milk. Monitor infants for sedation and hypotension.

DOSE ADJUSTMENTS IN ORGAN FAILURES

• Renal Impairment: Reduce dose; monitor for hypotension and bradycardia.
• Liver Impairment: Use with caution; no specific dose adjustment guidelines.
• Renal Replacement Therapy: No specific guidelines; monitor closely.

EVIDENCE

• Sedation in ICU: Meta-analysis of 8 RCTs showed clonidine reduces narcotic requirements but increases hypotension risk (Wang et al, 2021). Clonidine was used primarily as adjunctive sedation in 7 of the 8 RCTs. The A2B trial is yet to be published.
• Postoperative Sleep: Low-dose clonidine improves sleep quality in postoperative HDU patients. (Liu et al, 2024)

CONTROVERSIES

• Sedation Use: Debate over clonidine versus dexmedetomidine for ICU sedation due to differing side effect profiles
• Psychiatric Use: Variable evidence for off-label uses in psychiatric conditions (Naguy, 2016)
• Putative benefits in sepsis and cardiac bypass patients: decreased sympathetic outflow and catecholamine levels, improved vasoreactivity, decreased pro-inflammatory cytokines (e.g., TNF-α, IL-6), rand enal protection (Lankadeva et al, 2021)

PRACTICAL TIPS

• Beware of initial vasoconstriction: at high doses or when given IV, initial vasoconstriction and hypertension may occur due to direct stimulation of vascular alpha-2b receptors.
• Avoid Abrupt Discontinuation: Taper dose to prevent rebound hypertension and discontinuation syndrome (headache, anxiety, abdominal pain, tachycardia, and hypertension). Treat with clonidine re-initiation, and/or alpha-1 blockers in combination with beta-blockers (avoid monotherapy with beta-blockers, due to risk of unopposed alpha-1 effect of endogenous catecholamines)
• Monitor Blood Pressure: Regularly check BP and heart rate, especially when initiating or adjusting dose.
• Patient Education: Inform patients about potential for drowsiness and advise caution with driving.

TOXICOLOGY

• Risk Assessment:
  • >10 micrograms/kg: bradycardia and hypotension
  • >20 micrograms/kg: respiratory depression and apnoea
  • additive effects with other sedatives, antihypertensives, and anti-tachycardia agents
• Clinical Features: Drowsiness, miosis, bradycardia, hypotension.
• Management: Supportive care, atropine for bradycardia, IV fluids for hypotension. Naloxone may temporarily improve symptoms.
• see Clonidine toxicity for more detail.

REFERENCES

• Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill Education; 2018.
• Clonidine product information from TGA website. [pdf]
• Eberl S, Ahne G, Toni I, Standing J, Neubert A. Safety of clonidine used for long-term sedation in paediatric intensive care: A systematic review. Br J Clin Pharmacol. 2021 Mar;87(3):785-805. doi: 10.1111/bcp.14552. Epub 2020 Dec 23. PMID: 33368604.
• Glaess SS, Attridge RL, Christina Gutierrez G. Clonidine as a strategy for discontinuing dexmedetomidine sedation in critically ill patients: A narrative review. Am J Health Syst Pharm. 2020 Mar 24;77(7):515-522. doi: 10.1093/ajhp/zxaa013. PMID: 32086509.
• Lankadeva YR, Shehabi Y, Deane AM, Plummer MP, Bellomo R, May CN. Emerging benefits and drawbacks of α₂ -adrenoceptor agonists in the management of sepsis and critical illness. Br J Pharmacol. 2021 Mar;178(6):1407-1425. doi: 10.1111/bph.15363. Epub 2021 Feb 15. PMID: 33450087.
• Liu D, Hallt E, Platz A, Humblet A, Lassig-Smith M, Stuart J, Fourie C, Livermore A, McConnochie BY, Starr T, Herbst K, Woods CA, Pincus JM, Reade MC. Low-dose clonidine infusion to improve sleep in postoperative patients in the high-dependency unit. A randomised placebo-controlled single-centre trial. Intensive Care Med. 2024 Nov;50(11):1873-1883. doi: 10.1007/s00134-024-07619-w. Epub 2024 Sep 23. PMID: 39311905; PMCID: PMC11541301.
• Long N. Clonidine toxicity. LITFL. 2024. Available from: https://litfl.com/clonidine-toxicity/.
• Naguy A. Clonidine Use in Psychiatry: Panacea or Panache? Pharmacology. 2016;98(1-2):87-92. PMID: 272460.
• Schuler A, Yoon CH, Caffarini E, Heine A, Meester A, Murray D, Harding A. Alpha2 Agonist Use in Critically Ill Adults: A Focus on Sedation and Withdrawal Prevention. J Pharm Pract. 2025 Feb;38(1):155-167. doi: 10.1177/08971900241263171. Epub 2024 Jun 21. PMID: 38907529.
• Vanderah, T. W., & Katzung, B. G. (2024). Katzung’s Basic and Clinical Pharmacology (16th ed.). McGraw-Hill Education.
• Wang JG, Belley-Coté E, Burry L, Duffett M, Karachi T, Perri D, Alhazzani W, D’Aragon F, Wunsch H, Rochwerg B. Clonidine for sedation in the critically ill: a systematic review and meta-analysis. Crit Care. 2017 Feb 25;21(1):75. doi: 10.1186/s13054-017-1610-8. PMID: 28330506; PMCID: PMC5363026.