Specific alpha-2 agonist acting primarily in the locus coeruleus to increase conductance through K+ channels. 8 times more selective than clonidine. Acts on all 3 subtypes of alpha-2R (A, B, C)

Selective central α2 agonism
Inhibition of noradrenaline release in locus ceruleus
Peripherally at higher doses

selective modulation of GABA-A receptor (agonism)
(distinct from modulatory site for barbiturates and benzos, and GABA itself)
- Influx of Cl- into nerve cell
- Hyperpolarised, preventing conduction

Produces arousable sedation with minimal respiratory depression. Cardiovascular effects include bradycardia and hypotension, with transient hypertension possible during loading or higher exposure.

CNS
- Decreased sympathetic activity
- Decreased agitation
- Induces state resembling non-REM sleep without impairment of cognitive function. Easily roused but sedated.
- Analgesia produced in the posterior horns of the spinal cord, reduces need for opioid analgesia
- Decreases circulating cerebral catecholamines
- Decreases CBF/CMRO2/Mild decrease in ICP
- Decreases shivering

CVS: Decreased MAP and HR

Resp: Clinically insignificant increase in PaCO2 and decrease in RR

CNS: sedation: REM sleep-like state,min respiratory depression
Analgesia without as much confusion or disorientation as benzos. Pts easily aroused.
Spinal cord analgesia Decreases cerebral VO2, blood flow and ICP No antiemesis
CVS: Higher doses cause peripheral α2 effects – vasoconstriction,
followed by hypotension and bradycardia (Decreased sympathetic output)
Resp: Minimal Resp depression

CNS: Sedation and hypnosis
(Rapid distribution across BBB)
No analgesia
Burst suppression
Decreases cerebral VO2, blood flow and ICP
CVS: signifi¬cant drop in BP due to decreased TPR, but without a reflex tachycardia (infusion
rate dependent)
Resp: Dose dependent resp depression, apnoea
GIT: Anti-emetic

Intravenous administration bypasses an absorption phase. For procedural sedation, clinically effective sedation after a loading infusion is typically seen within about 10-15 minutes.

Without loading dose (commonly not used because of bradycardia), 30 minutes to reach effective concentration

A: Without loading dose (commonly not used because of bradycardia), 30 minutes to reach effective concentration

A: onset / duration 30 seconds / 3-10 minutes

Lipid soluble (rapid distribution)

pKa 11
very high lipid sol
Crosses placenta

95%

97-99%

2l/kg (steady state)

2-10L/kg
60l/kg after 10 day infusion
↓ in elderly

Hepatic via CYP and glucuronidation
inactive metabolites

Hepatic to partially inactive metabolites (water soluble sulfate and glucuronide conjugates(~50%)
Clearance > liver blood flow, ∴extrahepatic metabolism

Inactive metabolites Excreted in urine

Inactive metabolites
Excreted in urine

Excreted in urine

Urine (~88% as metabolites,40% as glucuronide)

Large variation in CSHT with infusion length (T1/2 5 minutes after 10 minutes IV, T1/2 240 minutes after 8 hour IV)

half life Biphasic: Initial 40 min; Terminal 4-7 hrs (up to 60hrs)

- Transient hypertension (due to peripheral smooth muscle α2B agonism) -> reflex bradycardia Later, hypotension and bradycardia. Rebound HTN on ceasing dose - Dry mouth - nausea

- Transient hypertension (due to peripheral smooth muscle α2B agonism) -> reflex bradycardia
Later, hypotension and bradycardia.
Rebound HTN on ceasing dose
- Dry mouth
- nausea

Transient hypertension (due to peripheral smooth muscle α2B agonism) -> reflex bradycardia
Later, hypotension and bradycardia.
Rebound HTN on ceasing dose
Dry mouth, nausea

Hypotension (baroreceptor sens.
blunted, decreased sympathetic tone). Painful on injection.
Propofol syndrome: Metabolic acidosis, hyperlipidaemia, myocardial failure, death- common in children

D-stereoisomer

Highly selective alpha-2 adrenoceptor agonist sedative with sympatholytic properties.

Central Antihypertensive

Sedative / Hypnotic

Sedative / Hypnotic

Sedation of ventilated adult ICU patients and procedural sedation of non-intubated adults. Also used for awake fibreoptic intubation in selected patients.

1. Sedation
2. Analgesia
3. Delirium prevention and management
4. Withdrawal syndromes
5. Perioperative sympatholytic

Short term sedation
Adjunct sedative when ventilator weaning in delirious and agitated patients

Short term sedation
Induction and maintenance of anaesthesia
Maintenance of sedation

Central alpha2 agonist
Greater selectivity for A2 than clonidine

2,6-di-isopropyl phenol Chemically inert phenolic derivative

-

Level 1

Level 1

Clear, colourless dexmedetomidine hydrochloride solution for intravenous use. Current Australian product information includes 200 micrograms in 2 mL vials.

Clear, colourless solution
IV only in Aus (PO overseas)
Comparitively expensive

Clear, colourless solution
IV only in Aus (PO overseas)
Comparitively expensive, D-stereoisomer

Milky white emulsion 1%
Soya bean lipid/Egg phosphatide
Sodium hydroxide
Weak org acid pKa 11- unionised

ICU sedation: maintenance infusion generally 0.2-1 microgram/kg/hour, titrated to the required level. A loading dose may be omitted when converting from another sedative. Procedural sedation: loading dose 1 microgram/kg over 10-20 minutes followed by 0.2-1 microgram/kg/hour, titrated to effect.

IV Infusion
Dose: 0.3-1mcg/kg/min

0.3-1mcg/kg/hr

Induction: 2-2.5mg/kg
Maintenance: 1-5mg/kg/hour
Both sig. less in critically ill