Alpha-2 Adrenoceptor Agonists
For exam revision only — verify all doses against the current BNF, the SmPC and your local formulary before clinical use. Disclaimer
Fundamentals
Overview
What are alpha-2 adrenoceptor agonists?
A group of centrally acting drugs used for their sedative and analgesic properties.
- Produce dose-dependent, rousable sedation resembling natural sleep, with minimal respiratory depression compared with traditional sedatives.
Which alpha-2 agonists are clinically available?
Several exist; only two are in regular UK use.
- Clonidine and dexmedetomidine - regularly used in the UK.
- Medetomidine, tizanidine, guanfacine - available but rarely used in this context.
Receptors & mechanism
What are the alpha-2 receptor subtypes and their functions?
G-protein-coupled receptors with three subtypes and distinct actions.
| Subtype | Location | Effect |
|---|---|---|
| Alpha-2A | Prefrontal cortex, locus coeruleus; spinal cord | Sedation, anxiolysis, analgesia; sympatholysis (hypotension, bradycardia, diuresis) |
| Alpha-2B | Peripheral blood vessels | Vasoconstriction |
| Alpha-2C | Striatum, hippocampus | Unclear; postulated anxiolytic |
Which receptors do clonidine and dexmedetomidine act on?
Both are non-pure alpha-2 agonists; their clinical profile reflects relative selectivity.
| Receptor | Location | Effect |
|---|---|---|
| Alpha-2 | Brain and periphery | Sedation, anxiolysis; reduced sympathetic outflow (hypotension, bradycardia) |
| Alpha-1 | Vascular smooth muscle | Peripheral vasoconstriction, hypertension |
| Imidazoline | Autonomic brain regions | Centrally mediated hypotension |
Where do common agents sit on the alpha-1 / alpha-2 selectivity spectrum?
From least to most alpha-2 selective: noradrenaline, adrenaline, dopamine, tizanidine, clonidine, mivazerol, guanfacine, medetomidine, dexmedetomidine.
- Dexmedetomidine is the most alpha-2 selective; clonidine is far less selective.
Comparison
Clonidine vs dexmedetomidine
What are the key clinical similarities and differences between clonidine and dexmedetomidine?
| Feature | Clonidine | Dexmedetomidine |
|---|---|---|
| Route | Oral, transdermal or IV | IV infusion only |
| Onset (IV) | ~10 min | <5 min |
| Terminal half-life | ~7 hr | ~2 hr |
| Protein binding | 20% | 90%+ |
| Volume of distribution | 1.7-2.5 L/kg | 1.3-2.4 L/kg |
| Metabolism / renal failure | 40% hepatic, 60% renal unchanged; accumulates in renal failure | Primarily hepatic to inactive metabolites; does not accumulate in renal failure |
| Selectivity (alpha-1:alpha-2) | 1:220 | 1:1,620 (more potent sedation) |
| Imidazoline effect | Greater - more hypotension | Lesser |
| Cost (approx) | ~£8/day | ~£100/day |
| Clinical use | Sedative, analgesic, anaesthetic adjunct; oral/transdermal allow non-ICU use | Mainly ICU/procedural sedation; better titratability, faster onset, more predictable haemodynamics, better in renal failure |
Clonidine
Monograph
Summary
Centrally-acting alpha-2 adrenoceptor agonist with sedative, anxiolytic, analgesic, sympatholytic and anti-shivering effects; opioid- and anaesthetic-sparing.
Indications & Dosing
- Premedication / sedation
Oral 1-5 micrograms/kg; IV 1-2 micrograms/kg (slow).
- Hypertension
Oral 50-100 micrograms BD-TDS.
- Neuraxial adjunct
Epidural / intrathecal 1-2 micrograms/kg.
- Anti-shivering
IV 0.5-1 microgram/kg.
Contraindications
- Severe bradyarrhythmia, sick sinus syndrome, or 2nd/3rd-degree AV block.
- Never stop abruptly after chronic use - rebound hypertension.
Formulations
- Tablets
25, 100, 300 microgram.
- Injection
150 microgram/mL.
Structure & Chemical Properties
- Class
Imidazoline derivative.
- pKa
8.3 (weak base).
- Lipid solubility
High - rapid CNS penetration.
The imidazoline ring confers central alpha-2 selectivity (~200:1 alpha-2:alpha-1).
Effect Timings
- Onset
IV 5-7 min; oral 30-60 min.
- Peak effect
Oral 60-90 min.
- Duration
6-10 h.
Absorption
- Oral bioavailability
75-95%.
Distribution
- Protein binding
20-40%.
- Vd
2 L/kg.
Metabolism
- Site
Hepatic (~50%).
- Metabolites
Inactive.
Elimination
- Terminal t-half
12-16 h (prolonged in renal impairment).
- Clearance
Renal - 40-60% excreted unchanged.
Mechanism of Action
Agonist at central pre-synaptic alpha-2 adrenoceptors (locus coeruleus, dorsal horn), reducing noradrenaline release and central sympathetic outflow; partial imidazoline-receptor binding contributes.
Systemic Effects
- CNS
- Sedation and anxiolysis with minimal respiratory depression.
- Analgesia and opioid-sparing.
- Reduces anaesthetic (MAC) requirements.
- CVS
- Bradycardia and reduced cardiac output.
- Hypotension from central sympatholysis; transient hypertension after rapid IV (peripheral alpha-2).
- RS
Minimal respiratory depression; airway reflexes preserved.
- GI
Dry mouth (reduced salivation); reduced GI motility.
- RenS
Mild diuresis and natriuresis.
- Other
Anti-shivering; attenuates opioid and alcohol withdrawal.
Side Effects & Toxicity
- Rebound hypertension on abrupt withdrawal.
- Bradycardia, hypotension, dry mouth, sedation.
- Overdose mimics opioid toxicity: bradycardia, hypotension, CNS depression.
Dexmedetomidine
Monograph
Summary
IV alpha-2 agonist with sedative and analgesic effects and minimal respiratory depression; less hypotension and a more predictable haemodynamic profile than clonidine; IV infusion only.
Indications & Dosing
- Critical-care sedation
IV loading 0.5-1.0 micrograms/kg (avoid if unstable); infusion 0.2-0.7 micrograms/kg/hr (up to 1.5). May reduce ventilation days and delirium; wean gradually.
- Adjunct to anaesthesia
IV loading 0.5-1.0 micrograms/kg; infusion 0.2-0.7 micrograms/kg/hr. Reduces MAC, opioid-sparing, reduces PONV and emergence delirium.
- Procedural / regional
Procedural sedation (e.g. awake intubation); prolongs regional/neuraxial blocks.
Contraindications
- Extreme caution in heart block, bradycardia, hypotension/hypovolaemia, severe LV dysfunction, PVD; and with beta-blockers/digoxin, TCAs, haloperidol (QT).
- Bolus dosing not recommended (vasoconstriction, hypertension, reflex bradycardia); avoid sudden withdrawal (rebound hypertension).
Formulations
- Injection (vials)
200 micrograms/2 mL, 400 micrograms/4 mL, 1000 micrograms/10 mL.
- Infusion
Dilute to 4 or 8 micrograms/mL in 0.9% saline or 5% glucose.
Structure & Chemical Properties
- Imidazoline derivative; dextroisomer of medetomidine; formula C13H16N2.
- Basic molecule, pKa 7.1; freely water-soluble with excellent fat solubility.
Effect Timings
- Onset / peak
<5 min / within 15 min.
- Context-sensitive half-time
Up to 4 hr after prolonged infusion.
Absorption
- Oral bioavailability
16% (extensive first-pass); primarily IV, can be intranasal.
Distribution
- Protein binding
94% (albumin and alpha-1-glycoprotein).
- Volume of distribution
1.31-2.46 L/kg; crosses blood-brain and placental barriers.
Metabolism
- Site
Primarily hepatic (glucuronidation + CYP450).
- Metabolites
Inactive; excreted renally (95%) and faecally (4%).
Elimination
- Distribution half-life
6 min.
- Terminal half-life
2 hr; does not accumulate in renal failure.
- Clearance
30-60 mL/min/kg.
Mechanism of Action
- Highly selective presynaptic alpha-2 agonist (alpha-1:alpha-2 1:1,620) acting on the locus coeruleus - more potent, more predictable sedation than clonidine.
- Limited alpha-1 and imidazoline activity (less than clonidine).
Systemic Effects
- CNS
Sedation/anxiolysis resembling natural sleep (rousable); decreases cerebral blood flow (not ICP); decreases IOP.
- CVS
Bolus: vasoconstriction, hypertension, reflex bradycardia (avoid). Therapeutic: bradycardia (~20%), vasodilation/hypotension (more predictable than clonidine); CO maintained.
- Respiratory
Minimal depression; no change in RR or PaCO2 at therapeutic doses.
- GI / Renal
Reduces gut motility, antisialogogue; diuresis (inhibits ADH).
Side Effects & Toxicity
- Excessive sedation, confusion, hallucinations; hypotension (transient hypertension on injection); bradycardia/heart block; dry mouth; constipation.
Questions
Exam focus
Alpha-2 agonists - exam question seeds (to build into the SBA/SOE bank)?
- Clonidine is an agonist (not antagonist) at imidazoline receptors - common SBA distractor.
- Clonidine oral bioavailability ~100%; dexmedetomidine only ~16% (so IV only).
- Dexmedetomidine needs dose reduction in hepatic (not renal) impairment; bolus not recommended.
- Clonidine must not be stopped abruptly (rebound hypertension); decreases cerebral blood flow but does NOT lower ICP.