Alpha-2 Adrenergic Agonists

(dexmedetomidine)

Pekka Talke MD
UCSF Faculty Development Lecture
Jan 2004
 Outline

• Overview of alpha-2 adrenoceptors and alpha-2

agonists
• Selected clinical effects
– Sedation
– Hemodynamics
– Ventilation
• Other effects mediated by alpha-2 agonists
• Practical points (Dosing)
• Discussion
 Outline

• Overview of alpha-2 adrenoceptors and alpha-2

agonists
• Selected clinical effects
– Sedation
– Hemodynamics
– Ventilation
• Other effects mediated by alpha-2 agonists
• Practical points (Dosing)
• Discussion
 Nine Adrenoceptors

• Alpha-1a, Alpha-1b and Alpha-1d

• Beta-1, Beta-2, Beta-3
• Alpha-2a, Alpha-2b and Alpha-2c
 Adrenoceptors

• Alpha-1a, Alpha-1b and Alpha-1d

• Beta-1, Beta-2, Beta-3
• Alpha-2a, Alpha-2b and Alpha-2c
– Central – Peripheral
– Presynaptic – Postsynaptic
– Extrasynaptic (vascular)
Alpha-Adrenoceptor Agonists

Alpha 1 • Norepinephrine
• Epinephrine
• Dopamine
• Tizanidine
• Clonidine
• MPV-2426
• Mivazerol
• Guanfacine
• Guanabenz
• Medetomidine
Alpha 2 • Dexmedetomidine
 Alpha-2 Agonists
H
Cl
N
N
Clonidine

N
Cl

H CH3

N Dexmedetomidine

CH3
N
CH3
 2 Agonists
Clonidine
• Selectivity: 2:1 250:1
• Imidazole derivate 16:1
• t1/2  10 hrs
• 2.5 L/kg
• PO, patch, epidural
• Antihypertensive
• Epidural formulation
Duraclon 1,000 ug/vial, IV
($50)
Dexmedetomidine
• Selectivity: 2:1 1620:1
• Imidazole derivate 31:1
• t1/2  2 hrs
• Vss 118 L (gets everywhere)
• 94% protein bound
• Eliminated by liver/kidney
• Effects own PK (V1?CO?)
• Sedative
• Only available in IV form
• Precedex 200 ug/vial ($55)
 Outline
• Overview of Alpha-2 adrenoceptors and agonists
• Selected clinical effects
– Sedation
– Hemodynamics
– Ventilation
• Other effects mediated by alpha-2 agonists
• Practical points (Dosing)
 Sedation

• Dose dependent
• Minimal respiratory depression
• Arousable
• Known action
– Hyperpolarization of LC neurons
– 2A-receptor subtype
• Resembles natural sleep (ICU?)
• Reversible (atipamezole)
• Amnesia?
 Sedation Scores
Maximum Tolerable Dose Study
25

20

OAA/S 15

§
10

100

§
75

VAS 50

25

0
§Significant change in variable during Baseline 0.7 1.2 1.9 3.2 5.1 8.4 14.7
dexmedetomidine infusions.
Adapted from Ebert et al. Anesthesiology.
2000;93:389. Plasma Dexmedetomidine (ng/ml)
 Arousability From Sedation
During Dexmedetomidine Infusion
Low
Placebo
Moderate
110
100
90
BIS 80
70
60
50
pre 10 20 30 40 50 60 tests 0.5 1 tests 1.5 2 3 4 tests

Infusion Period (min) Recovery Period (hr)

Hall. Anesth Analg. 2000;90:701.

 Arousability From Sedation During
Dexmedetomidine Infusion
Just prior to cognitive and cold pressor testing
During cognitive and cold pressor testing

100

80
BIS
60

40
Placebo 0.2 0.6
Dexmedetomidine Infusion
(µg/kg-1/hr-1)
Hall. Anesth Analg. 2000;90:701.
 Comparison of Equi-Sedative Doses of
Midazolam and Dexmedetomidine on Task
Performance in Humans

110

100

90
% Hits

Task and noise

80
Task alone
70

60

50
Placebo Dex Midazolam
Drug
 Anesthesia/Analgesia Sparing

• Intraop, postop
• Induction agents, inhalation anesthetics,
opioids, midazolam
• 40% with dexmedetomidine (0.6-0.8
ng/mL), up to 90%
• 40% with clonidine (5 mcg/kg po or IV)
 Sedation

• Goal is to have a comfortable, calm patient

who is arousable and cooperative
• Patient who is not arousable should have
the dose reduced.
• Arousability a test for appropriate sedation
(EEG/BIS)

• Patient too awake - needs more (clonidine)

 Sedation

• No central respiratory depression. However

sedation may cause upper airway
obstruction.

• Very synergistic with other sedatives

• Length of infusion: 24 hr vs ?? tolerance, cortisol,

rebound.
 Sedation

• Typical doses (target plasma levels 0.3-1.2 ng/ml):

– 0.5 ug/kg load, 0.5 ug/kg/hr infusion
– 1.0 ug/kg load, 0.7 ug/kg/hr infusion
– Increase dose by bolus/infusion
– Load only - short procedures
– Patients with high sympathetic activity may need
very high doses. Most PD, dosing studies done in
unstimulated volunteers.
 Outline
• Overview of alpha-2 adrenoceptors and agonists
• Physiologic effects mediated by alpha-2 agonists
• Selected clinical effects
– Sedation
– Hemodynamics
– Ventilation
• Practical points (Dosing)
 Hemodynamic effects
• Combination of effects mediated by:
– Reduction of central SNS activity (alpha-2a)
– Reduction of presynaptic NE release (alpha-2a and c)
– Stimulation of VSM cells (alpha-2b)
– Stimulation of endothelium
– Stimulation of central imidazoline receptors
– Some vagomimetic activity
 Heart Rate Response
90

80

70

beats/min
60

50

40

Time
 HR effects
• Bradycardia does not typically progress to a clinically significant
problem, unless patient has coexisting disease and will not
tolerate bradycardia.

• Like total spinal. Once the SNS activity is gone…

• Baroreflexes are reset, but intact - hypertension will reduce HR

further.

• Observed asystole/sinus pauses have developed in healthy

unstimulated volunteers at any dex plasma level, after a vagal
stimulus. Unopposed vagal stimulus.
 HR effects

• Intraoperative use of dexmedetomidine have

resulted in increased treatment of
bradycardia.

• Heart blocks have been observed

intraoperatively (no catechols?)

• Postoperative treatment of bradycardia is

rare (catechols)
 HR effects

• Average response is a 20% reduction in HR

• Volunteers with low resting heart rates have smaller

HR responses than patients with high HRs

• Treatment of bradycardia:
– Normal response to atropine and glycopyrrolate
– Be cautious-coronary perfusion.
 Heart rate Response MTD
65

60

55

50
HR

45

4 CO

0.0 0.5 0.8 1.2 2.0 3.2 5.0

ng/ml
 Hemodynamic Response
(Single Patient)
HR
120

100 DP08

80

60

40
200
SBP
180
160
140
120
100
80
60
40
ICP
30

25

20
15

10

5
 Effect on Heart Rate
Propofol
130
Dexmedetomidine
120

110

100

Heart Rate 90
(beats min-1)
80

70

60

50
0 1 2 3 4 5 6 7 8 +4 +8 +12 +16 +20 +24

Infusion Time (hr)

Sedative drug
discontinued
Venn RM, Grounds RM. Br J Anaesth. 2001;87:684-690.
 Blood Pressure Response

100

95

90

85
MAP
80
mm Hg
75

70

65

60

Time
 Hemodynamic Response MTD

2500
2250
2000
1750 SVR
1500
1250
1000

100

80
SBP

60
0.0 0.5 0.8 1.2 2.0 3.2 5.0
ng/ml
 Hemodynamic Response
(Single Patient)
HR
120

100 DP08

80

60

40
200
SBP
180
160
140
120
100
80
60
40
ICP
30

25

20
15

10

5
 Effect on Blood Pressure
175 Propofol
Dexmedetomidine

150

Arterial 125
pressure
(mm Hg) 100

75

50

0 1 2 3 4 5 6 7 8 +4 +8 +12 +16 +20 +24

Infusion Time (hr)
Sedative drug
discontinued
Venn RM, Grounds RM. Br J Anaesth. 2001;87:684-690.
 Alpha-2b / Vasoconstriction

• Alpha-2b adrenoceptors at vascular smooth

muscle cells mediate vasoconstriction

• Inverse relationship between arterial

diameter and alpha-2 ARs.

• “instantaneous” compared to the central

sympatholytic effect
Clonidine/ General anesthesia
nA
9000

8500 VASOCONSTRICTION

8000 awake VASODILATION

7500

7000

6500

6000

5500 anesthetized
5000

4500 0.3 0.45 0.68 1.0 1.5 2.25

Clonidine Target levels (ng/ml)
4000
Time (min)
 Dexmedetomidine/ General anesthesia

% %
DEXMEDETOMIDINE SALINE
35 35
30 LTF 30 LTF
25 25
20 20
15 15
10 10
5 5
0 0
-5 -5
-10 105 -10 105
SBP 100 SBP 100
95 95
90 90
85 85
0.075 0.15 0.3 0.60 80 80
Dexmedetomidine Levels (ng/ml)
75 75
Time (min) Time (min)
 Dexmedetomidine/ Axillary block

% Percent Change in LTF data mmHg

60 140
VASOCONSTRICTION 130 SBP
40 120
VASODILATION 110
20
BLOCKED ARM
100
0 bpm 90
UNBLOCKED ARM 80 HR
-20 70
-40 0.075 0.15 0.3 0.6 60
Dexmedetomidine Levels (ng/ml) 50 0.075 0.15 0.3 0.6
-60 40
Time (min) Time (min)
 Common observation

• BP increased when I gave dex, What should

I do?

• Why: Propofol, general anesthesia, epidurals

reduce SNS activity/tone. Thus,
vasoconstriction may dominate.

• Either reduce the dose or switch to another

drug.
 Outline
• Overview of Alpha-2 adrenoceptors and agonists
• Selected clinical effects
– Sedation
– Hemodynamics
– Ventilation
• Other effects mediated by alpha-2 agonists
• Practical points (Dosing)
 Effect on Ventilation (Alpha-2)

• Clonidine, dexmedetomidine
– Minimal effect on RR, VE, Pa CO2,
– Small decrease in VE/ET CO2
• No potentiation of opioid-induced respiratory
depression
• Sedation: upper airway obstruction
• Irregular RR with large boluses
 Respiratory Response
Maximum Tolerable Dose Study
120
PaO2
100
80
mm Hg 60
40
20
0
Baseline 0.5* 0.8* 1.25* 2.0* 3.2* 5.0* 8.0*

120 PaCO2
100
80
mm Hg † † †
60
40
20
0
Baseline 0.5* 0.8* 1.25* 2.0* 3.2* 5.0* 8.0*

30 Respiratory Rate
25 † †
†
20
breaths/min 15
10
5
0
Baseline 0.5* 0.8* 1.25* 2.0* 3.2* 5.0* 8.0*
Data are mean ± SEM.
*Target dexmedetomidine (ng/mL).
†P<0.05 compared with baseline values.
Adapted from Ebert et al. Anesthesiology. 2000;93:389.
 Respiratory Response MTD

50

CO2
45

40
25

20
RR

15

10
0.0 0.5 0.8 1.2 2.0 3.2 5.0
ng/ml
 Outline
• Overview of Alpha-2 adrenoceptors and agonists
• Selected clinical effects
– Sedation
– Hemodynamics
– Ventilation
• Other effects mediated by alpha-2 agonists
• Practical points (Dosing)
Alpha-2 AR Mediated Responses

– Numerous alpha-2 AR mediated responses

– Different dose response curve for each

 2-Receptor Subtypes
Physiology of 2 Andrenoceptors

2 A
Anxiolysis
2A 2 C

X
? 2 B

2 B

2 A

? 2 B 2 A
Effects of Alpha-2 Agonists

– Endocrine
•  NE release
•  insulin release
•  cortisol release
•  GH release

– Baroreflexes stay intact (reset)

– Normal response to vasoactive drugs
– Attenuates stress response
Effects of Alpha-2 Agonists

– No effect on ICP
– Reduces IOP
– No effect on relaxants
– Prolongs local anesthetic action
– Decreases metabolism
– Decreases oxygen consumption
Effects of Alpha-2 Agonists

– Dry mouth (awake fibers)

– Decreases bowel motility
– Decreases psychomotor performance
– Not amnestic
– Slows EEG
– Prevents opioid induced rigidity
– Neuro/cardiac protection?
 Side Effects

• Sinus pause/arrest
• Orthostatic hypotension
• Dry mouth
• Vasoconstriction
 Outline

• Overview of alpha-2 adrenoceptors and alpha-2

agonists
• Selected clinical effects
– Sedation
– Hemodynamics
– Ventilation
• Other effects mediated by alpha-2 agonists
• Practical points (Dosing)
• Discussion
 Patient Selection

• High sympathetic activity

• Agitated/anxious
• With discomfort
NOT

• Low blood pressure

• Hypovolemic/shock
• Conduction defects
 Dosing

• Dexmedetomidine
– 10 min loading infusion 0.5-1.0 ug/kg
– 0.2-0.7 ug/kg/hr infusion
– Effects in 5-10 min, reduced in 30-60 min
• Clonidine
– 10 min loading infusion 3-5 ug/kg
– 0.3 ug/kg/hr infusion
– Effects in 5-10 min iv, in 60-90 min po
 My favourite use

• Transition from intraop to postop period by

administering dexmedetomidine during the
last 30 min of surgery, while reducing other
anesthetics

• Limited by PACU/ICU nurses who are

unfamiliar with managing the infusion

• NOT a do all drug! Still need some narcotics.

No cross tolerance with opioids
 Alpha-2 agonist development
(where to look for the literature)

• Clonidine 1960 (nasal decongestant)

• Medetomidine (vetenary use, early literature)
– Levomedetomidine inactive
• Dexmedetomidine 1980’s (lots of studies):
– Premedication
– Anti-ischemic agent
– Anesthetic adjunct (intraop)
– ICU sedation
• Mivazerol (development stopped)
• MPV 2426 (polar compound for pain)
• Future: Subtype selective agonists/antagonists
 Outline

• Overview of alpha-2 adrenoceptors and alpha-2

agonists
• Selected clinical effects
– Sedation
– Hemodynamics
– Ventilation
• Other effects mediated by alpha-2 agonists
• Practical points (Dosing)
• Discussion