increases the sensitivity GABAA receptors which open (via GABA) and allow Cl influx
causing hyperpolarisation
- Influx of Cl- into nerve cell
- Hyperpolarised, preventing conduction

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

CNS: Sedative, reduces epileptiform activity,
increases confusion and disorientation, amnesic properties more prominent than
sedative eff¬ects
CVS: minor hypotension has been reported

Resp: respiratory depression - synergistic with opioids

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

A : IV,PO,In,IM
poor oral bioavailability 45%

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

lipid soluble at physiological pH (pKa 6.5).
high lipid sol crosses BBB

Lipid soluble (rapid distribution)

Approximately 96% protein-bound in plasma.

highly protein bound (95%)

95%

95%

Volume of distribution approximately 0.8-1.5 L/kg, increasing to about 3.1 L/kg in critically ill patients.

small-mod Vd = 1-2 L/kg
high lipid sol crosses BBB

1-2 L/kg

2l/kg (steady state)

hepatic via CYP3A4, and glucuronidation
active metabolite

Hepatic via CYP and glucuronidation
inactive metabolites

excreted in urine (as glucuronide conjugated metabolites)

Inactive metabolites Excreted in urine

Inactive metabolites
Excreted in urine

Excreted in urine

half life 1-4 hrs
prolonged in cirrhosis, CRF, CCF, obesity, elderly

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

Respiratory depression and excessive sedation with overdosage
Same CYP as alfentanil (increases effect)

Respiratory depression and excessive sedation with overdosage
Same CYP as alfentanil (increases e¬ffect)

- 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

- Imidazole ring in its structure - Accounts for water solubility And rapid metabolism
- 2-3x potent Diazepam

D-stereoisomer

Anticonvulsant Sedative-Hypnotic

Anticonvulsant
Sedative-Hypnotic

Sedative / Hypnotic

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

Central Antihypertensive

Sedative / Hypnotic

Sedative, amnesic+ anxiolytic,
antiepileptic

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

- Benzodiazepine
- Imidazole ring in its structure - Accounts for water solubility And rapid metabolism
- 2-3x potent Diazepam

Central alpha2 agonist
Greater selectivity for A2 than clonidine

Level 1

-

Level 1

Clear solution pH 3.5 (IV/IM), Tablet
pKa 6.5 – 89% un-ionized

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

2-2.5mg initially then 1mg boluses to eff¬ect

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