RESOURCES

Review Articles

Khan, Anaesthesia (1999); Alpha-2 and imidazoline receptor agonists
Giovannitti, Anesthesia Progress (2015); Alpha-2 Adrenergic Receptor Agonists: A Review of Current Clinical Application
Maud, Clin Pharmacokinet (2017); Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine
Jamadharkana, J Anaesth Clin Pharmacol (2010); Clonidine in Adults as a Sedative Agent in the Intensive Care Unit
Fernandes, Biomed J Sci&Tech Res (2018); Clonidine in Anesthesiology: A Brief Review
Kaur, Anesthesia: Essays and Researches (2011); Current role of dexmedetomidine in clinical anesthesia and intensive care
Scott-Warren, BJA Ed (2016); Dexmedetomidine: its use in intensive care medicine and anaesthesia

OBJECTIVES & QUESTIONS

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Overview, Mechanisms & Effects

What are alpha-2 agonists?

A group of centrally acting drugs used primarily for their sedative and analgesic properties
Produce dose-dependent interactive sedation that resembles natural sleep with minimal respiratory depression compared to traditional sedatives

What are the clinically available alpha-2 agonists?

Several alpha-2 agonists are available:
- Clonidine
- Dexmedetomidine
- Medetomidine
- Tizanidine
- Guanfacine
Of these, only clonidine and dexmedetomidine are regularly used in the UK

What are the alpha-2 receptors, and what are their functions?

Belong to a family of membrane-bound guanine nucleotide-binding protein-coupled receptors
Consists of three main subtypes with different actions:

Receptor

Location

Effect

Alpha-2A

Prefrontal cortex and locus coeruleus of the brain

Suppresses neuronal firing reducing the activity of ascending noradrenergic pathways:
- Sedative and anxiolytic effects
Directly stimulate presynaptic α2A- and α2C-adrenoceptors in the spinal cord, thereby inhibiting the firing of nociceptive neurons
- Analgesic (anti-nociceptive) effect
Reduces sympathetic outflow (sympatholytic action):
- Reduces sympathetic tone (promotes hypotension)
- Reduces cardiac sympathetic activity (reduces heart rate, cardiac output and myocardial oxygen consumption)
- Reduces renal sympathetic activity (inhibits renin and vasopressin release, promotes diuresis)

Alpha-2B

Peripheral blood vessels

Vasoconstriction

Alpha-2C

Striatum and hippocampus of the brain

Unclear clinical effects
Postulated to have anxiolytic effects

Which receptors do clonidine and dexmedetomidine act on?

Clonidine and dexmedetomidine are not pure alpha-2 adrenoceptor agonists, but also act at several different receptors
Specific drug effects depend on the relative selectivity for each receptor type:

Receptor

Location

Effect

Alpha-2

Widespread throughout the brain and periphery

Primarily sedation and anxiolysis
Reduce sympathetic outflow resulting in hypotension and bradycardia

Alpha-1

Vascular smooth muscles

Peripheral vasoconstriction & hypertension

Imidazoline

Autonomic regions of the brain

Centrally mediated hypotension

Where do common alpha-2 agonists sit in the spectrum of alpha-1 and alpha-2 agonism?

Comparison

What are the key clinical similarities and differences between clonidine and dexmedetomidine?

Clonidine

Dexmedetomidine

Route of Administration

Administered orally, transdermally, or intravenously

Administered via intravenous infusion only

Pharmacokinetics

Onset of action 10 minutes IV
Terminal half-life ~7 hours
20% bound to plasma proteins
Volume distribution of 1.7–2.5 L/kg
40% hepatically metabolised to inactive metabolites
60% excreted renally unchanged
Accumulates in renal failure

Onset of action <5 minutes IV
Half-life 2 hours
90% bound to plasma proteins
Volume distribution of 1.3–2.4 L/kg
Primarily hepatically metabolised to inactive metabolites
Does not accumulate in renal failure

Mechanism of Action

Lesser selectivity for α2-adrenoceptors (α2:α1 ratio 220:1)
Greater agonism at imidazoline receptors and therefore tends to cause more hypotension

Greater selectivity for α2-adrenoceptors (α2:α1 ratio 1,620:1) producing more potent sedation
Lesser action on imidazoline receptors

Price

Cheap - estimated cost £8/day

Expensive - estimated cost £100/day

Clinical Uses

Used as sedative, analgesic and anaesthetic adjunct
Availability of oral and transdermal formulations makes it easier to use in non-intensive care settings

Primarily used as a sedative for procedures or intensive care
Better suited for intensive care than clonidine due to:
- Increased titratability
- Rapid onset of sedative effect
- Predictable haemodynamic response with less prominent hypotension and bradycardia
- Better pharmacokinetic profile in renal failure

Clinical Essentials

Overview

Alpha-2 agonist with sedative and analgesic effects
Produces sedation without significant effect on respiratory drive
Used for multiple indications across anaesthesia, critical care and pain management
An older drug which has been superseded by dexmedetomidine for some indications

Alpha-2 agonist with sedative and analgesic effects
Produces sedation without significant effect on respiratory drive
Used for multiple indications across anaesthesia, critical care and pain management
An older drug which has been superseded by dexmedetomidine for some indications

Indications & Dosing

Sedation on critical care

Sedation of intubated and mechanically ventilated patients as an adjunct to other sedatives
Treatment of agitated and delirious patients
Must be weaned gradually

IV infusion: 0.5-1.0 mcg/kg/hr
IV/PO: 50-200 mcg QDS

Adjunct to anaesthesia

Reduces MAC of volatile agents

IV: 1–2 mcg/kg

Adjunct to perioperative analgesia

IV: 1–2 mcg/kg

Adjunct to regional anaesthesia

Prolongs duration of effect
Useful in peripheral nerve, epidural, caudal and spinal blocks

Anxiolysis (Premedication)

May be a useful in both children and adults (though onset is slow)

PO: 4 mcg/kg

Antihypertensive

Medical use is limited by severe rebound hypertension following discontinuation
May be useful for hypotensive anaesthesia

Alcohol & opiate withdrawal

PO: 0.6-1.2 mg/day in divided doses

Postoperative shivering

IV/PO: up to 0.5 mcg/kg (low dose)

Migraine prophylaxis

PO: low dose

Contraindications

No definitive contraindications
Extreme caution should be exercised in patients with:
- Heart block
- Bradycardia
- Hypotension or hypovolaemia
- Severe ventricular dysfunction
- Peripheral vascular disease
- Concomitant use of:
  - Beta-blockers (bradycardia)
  - Tricyclic antidepressants (counteract effect)
  - Digoxin (bradycardia)
  - Haloperidol (prolongation of QT interval)
Sudden withdrawal should be avoided due to the risk of rebound hypertension

No definitive contraindications
Extreme caution should be exercised in patients with:
- Heart block
- Bradycardia
- Hypotension or hypovolaemia
- Severe ventricular dysfunction
- Peripheral vascular disease
- Concomitant use of:
  - Beta-blockers (bradycardia)
  - Tricyclic antidepressants (counteract effect)
  - Digoxin (bradycardia)
  - Haloperidol (prolongation of QT interval)
Sudden withdrawal should be avoided due to the risk of rebound hypertension

Formulation

Intravenous

150mcg in 1ml vial

Oral

25 – 150 mcg tablets

Transdermal

100-300 mcg/24hrs patches

Preparation

IV Injection:
- May be given undiluted or diluted to aid slow administration
IV infusion:
- Suggested standard infusion in critical care
- Dilute to 15mcg/ml or 30mcg/ml
- Sodium chloride 0.9% or glucose 5% can be used

IV Injection:
- May be given undiluted or diluted to aid slow administration
IV infusion:
- Suggested standard infusion in critical care
- Dilute to 15mcg/ml or 30mcg/ml
- Sodium chloride 0.9% or glucose 5% can be used

Physico-Chemical Properties

Structure & Chemical Properties

Molecular Structure

Imidazoline derivative
Chemical name is 2-((2,6-dichlorophenyl) amino)-2-imidazoline hydrochloride
Chemical formula is C₉H₉Cl₂N₃

Chemical Properties

Basic molecule with pKa 8.06
Highly lipophilic due to dichlorophenyl ring

Pharmacokinetics

Effect Timings

Onset of Effect

IV: 5-7 minutes
PO: 1-2 hours

Duration of Effect

IV: 3-7 hours
PO: Up to 8 hours

Absorption

Oral Bioavailability

70-100%

Comments

Absorption is rapid, with peak plasma levels within 1-2 hours

Distribution

Protein Binding

20%

Volume of Distribution (V_d)

1.7–2.5 L/kg

Comments

Readily crosses the blood-brain and placenta barriers

Metabolism

Site

Around 40% metabolised in the liver
Remaining is excreted unchanged by the kidneys

Metabolites

Produces inactive metabolites
Excreted renally (95%) and faecally (4%)

Elimination

Distribution Half-Life

20 minutes

Terminal Half-Life

~7 hours
Significantly increased in renal failure (up to 23 hours)

Clearance

1.9–4.3 ml/min/kg

Pharmacodynamics

Mechanism of Action

Selective agonist at presynaptic alpha-2 adrenoceptors:
- Less selective than dexmedetomidine with ratio of alpha-1:alpha-2 1:200
- Acts particularly on the locus coeruleus in the ﬂoor of the fourth ventricle, producing depression of thalamic transmission to the cerebral cortex
- Primarily responsible for sedation, anxiolysis and analgesia
- Reduce sympathetic outflow resulting in hypotension and bradycardia
Some activity at alpha-1 receptors:

Some activity at imidazole receptors:

Produces centrally mediated hypotension

Selective agonist at presynaptic alpha-2 adrenoceptors:
- Less selective than dexmedetomidine with ratio of alpha-1:alpha-2 1:200
- Acts particularly on the locus coeruleus in the ﬂoor of the fourth ventricle, producing depression of thalamic transmission to the cerebral cortex
- Primarily responsible for sedation, anxiolysis and analgesia
- Reduce sympathetic outflow resulting in hypotension and bradycardia
Some activity at alpha-1 receptors:

Some activity at imidazole receptors:

Produces centrally mediated hypotension

Systemic Effects

CNS

Sedation and anxiolysis:
- Effects comparable to normal sleep
- May be more co-operative and communicative than patients sedated with other drugs
Decreases cerebral blood flow, but does not lower intracranial pressure
Decreases intraocular pressure

AS

Decreases gastric and small bowel motility
Acts as an antisialogogue

RS

Very minimal respiratory depression
At therapeutic doses no change in respiratory rate or PaCO2

CVS

Usually exerts biphasic effect on blood pressure:
- Causes hypotension at lower doses due to predominate effects on imidazoline and alpha-2 receptors
- Higher doses stimulate peripheral alpha-1 receptors, thereby causing vasoconstriction, which may increase blood pressure
May cause a decrease in heart rate (average response 20% decrease)
No effect on cardiac contractility, and the cardiac output is well maintained

RenS

Acts as a diuretic due to inhibition of ADH

Side Effects & Toxicity

Excessive sedation, confusion, hallucinations
Hypotension (initial transient hypertension on injection)
Bradycardia, heart block
Dry mouth
Constipation

Excessive sedation, confusion, hallucinations
Hypotension (initial transient hypertension on injection)
Bradycardia, heart block
Dry mouth
Constipation

Clinical Essentials

Overview

Intravenous Alpha-2 agonist with sedative and analgesic effects
Produces sedation without significant effect on respiratory drive
Produces less hypotension and has a more predictable haemodynamic profile than clonidine
Primarily used in intensive care and anaesthesia due to the requirement for administration as an intravenous infusion

Intravenous Alpha-2 agonist with sedative and analgesic effects
Produces sedation without significant effect on respiratory drive
Produces less hypotension and has a more predictable haemodynamic profile than clonidine
Primarily used in intensive care and anaesthesia due to the requirement for administration as an intravenous infusion

Indications & Dosing

Sedation on critical care

Sedation of intubated and mechanically ventilated patients as a sole agent or as an adjunct to others:
- May reduce days of ventilation
- May reduce rates of delirium
Treatment of agitated and delirious patients
Must be weaned gradually

IV loading: (usually avoided if critically ill or haemodynamically unstable) 0.5-1.0 mcg/kg
IV Infusion: 0.2-0.7 mcg/kg/hr (can increase cautiously to 1.5 mcg/kg/hr)

Adjunct to anaesthesia

Reduces MAC of volatile agents
Has some analgesic properties (reduces opiate requirement)
Reduces postoperative nausea
Reduces emergence delirium

IV loading: 0.5-1.0 mcg/kg
IV Infusion: 0.2-0.7 mcg/kg/hr (can increase cautiously to 1.5 mcg/kg/hr)

Procedural sedation

Useful for awake intubation

Adjunct to regional anaesthesia

Prolongs duration of effect
Useful in peripheral nerve, epidural, caudal and spinal blocks

Contraindications

No definitive contraindications
Extreme caution should be exercised in patients with:
- Heart block
- Bradycardia
- Hypotension or hypovolaemia
- Severe ventricular dysfunction
- Peripheral vascular disease
- Concomitant use of:
  - Beta-blockers (bradycardia)
  - Tricyclic antidepressants (counteract effect)
  - Digoxin (bradycardia)
  - Haloperidol (prolongation of QT interval)
Caution should be exercised when using as a sole sedative agent in patients <65 years of age (signal toward worse outcomes)
Sudden withdrawal should be avoided due to the risk of rebound hypertension

No definitive contraindications
Extreme caution should be exercised in patients with:
- Heart block
- Bradycardia
- Hypotension or hypovolaemia
- Severe ventricular dysfunction
- Peripheral vascular disease
- Concomitant use of:
  - Beta-blockers (bradycardia)
  - Tricyclic antidepressants (counteract effect)
  - Digoxin (bradycardia)
  - Haloperidol (prolongation of QT interval)
Caution should be exercised when using as a sole sedative agent in patients <65 years of age (signal toward worse outcomes)
Sudden withdrawal should be avoided due to the risk of rebound hypertension

Formulation

Intravenous

Vial: 200mcg/2ml, 400mcg/4ml or 1000mcg/10ml

Preparation

Suggested standard infusion in critical care
Dilute to 4mcg/ml or 8mcg/ml
Sodium chloride 0.9% or glucose 5% can be used

Suggested standard infusion in critical care
Dilute to 4mcg/ml or 8mcg/ml
Sodium chloride 0.9% or glucose 5% can be used

Physico-Chemical Properties

Structure & Chemical Properties

Molecular Structure

Imidazoline derivative
Dextroisomer of the veterinary sedative medetomidine
Chemical name is (S)-4-[1-(2,3-Dimethylphenyl)ethyl]-3H-imidazole
Chemical formula is C₁₃H₁₆N₂

Chemical Properties

Basic molecule with pKa 7.1
Freely soluble in water, but also has excellent fat solubility

Pharmacokinetics

Effect Timings

Onset of Effect

<5 minutes following loading & infusion)

Peak of Effect

Within 15 minutes following loading & infusion

Duration of Effect

Given as infusion

Context Sensitive Half Time

Favourably short, up to 4 hours after prolonged infusion

Absorption

Oral Bioavailability

16%

Comments

Extensive first-pass metabolism
Primarily limited to intravenous use but can be given intranasally

Distribution

Protein Binding

94%
(albumin and α1-glycoprotein)

Volume of Distribution (V_d)

1.31–2.46 L/kg

Comments

Readily crosses the blood-brain and placenta barriers

Metabolism

Site

Primarily metabolised in the liver
Metabolised via glucuronidation and cytochrome 450 hydroxylation

Metabolites

Metabolised to inactive metabolites
Excreted renally (95%) and faecally (4%)

Elimination

Distribution Half-Life

6 minutes
(rapid distribution phase)

Terminal Half-Life

2 hours

Clearance

30-60 ml/min/kg

Pharmacodynamics

Mechanism of Action

Selective agonist at presynaptic alpha-2 adrenoceptors:
- More selective than clonidine with ratio of alpha-1:alpha-2 1:1,620
- More pronounced effect on central alpha-2 receptors
- Acts particularly on the locus coeruleus in the ﬂoor of the fourth ventricle, producing depression of thalamic transmission to the cerebral cortex
- Primarily responsible for sedation, with more potent sedative effect than clonidine
- Reduces sympathetic outflow resulting in hypotension and bradycardia
Some limited activity at alpha-1 receptors
Some limited activity at imidazole receptors (though less than clonidine)

Selective agonist at presynaptic alpha-2 adrenoceptors:
- More selective than clonidine with ratio of alpha-1:alpha-2 1:1,620
- More pronounced effect on central alpha-2 receptors
- Acts particularly on the locus coeruleus in the ﬂoor of the fourth ventricle, producing depression of thalamic transmission to the cerebral cortex
- Primarily responsible for sedation, with more potent sedative effect than clonidine
- Reduces sympathetic outflow resulting in hypotension and bradycardia
Some limited activity at alpha-1 receptors
Some limited activity at imidazole receptors (though less than clonidine)

Systemic Effects

CNS

Sedation and anxiolysis:
- Effects comparable to normal sleep
- May be more co-operative and communicative than patients sedated with other drugs
Decreases cerebral blood flow, but does not lower intracranial pressure
Decreases intraocular pressure

AS

Decreases gastric and small bowel motility
Acts as an antisialogogue

RS

Very minimal respiratory depression
At therapeutic doses no change in respiratory rate or PaCO2

CVS

May cause vasoconstriction, hypertension and reflex bradycardia if given as a bolus (boluses not recommended)
At therapeutic doses central effect on sympathetic outflow causes:
- Bradycardia (average response 20% decrease)
- Vasodilation and hypotension (effects more predictable than clonidine)
No effect on cardiac contractility, and the cardiac output is well maintained

RenS