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
Alpha 2
•
•
•
•
•
•
•
•
•
•
•
Norepinephrine
Epinephrine
Dopamine
Tizanidine
Clonidine
MPV-2426
Mivazerol
Guanfacine
Guanabenz
Medetomidine
Dexmedetomidine
Alpha-2 Agonists
H
Cl
N
CH3
CH3
Clonidine
N
Dexmedetomidine
N
Cl
H
N
CH3
N
2 Agonists
Clonidine
Dexmedetomidine
• Selectivity: 2:1 250:1
• Selectivity: 2:1 1620:1
• 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)
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
5
100
§
75
VAS
50
25
§Significant change in variable during
dexmedetomidine infusions.
Adapted from Ebert et al. Anesthesiology.
2000;93:389.
0
Baseline
0.7
1.2
1.9
3.2
5.1
8.4
14.7
Plasma Dexmedetomidine (ng/ml)
Arousability From Sedation
During Dexmedetomidine Infusion
Placebo
110
Low
Moderate
100
90
BIS
80
70
60
50
pre 10 20 30 40 50 60 tests 0.5
Infusion Period (min)
Hall. Anesth Analg. 2000;90:701.
1 tests 1.5
2
3
Recovery Period (hr)
4 tests
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
% Hits
100
90
Task and noise
Task alone
80
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
6
5
CO
4
3
0.0
0.5
0.8
1.2
ng/ml
2.0
3.2
5.0
Hemodynamic Response
(Single Patient)
120
HR
DP08
100
80
60
40
200
180
160
140
120
100
80
60
40
30
25
20
15
10
5
SBP
ICP
Effect on Heart Rate
Propofol
Dexmedetomidine
130
120
110
100
Heart Rate
(beats min-1)
90
80
70
60
50
0
1
2
3
Infusion
4
5
6
7
8
+4
+8 +12 +16 +20 +24
Time (hr)
Sedative drug
discontinued
Venn RM, Grounds RM. Br J Anaesth. 2001;87:684-690.
Blood Pressure Response
100
95
90
85
MAP
mm Hg
80
75
70
65
60
Time
Hemodynamic Response
2500
2250
2000
1750
SVR
1500
1250
1000
100
80
SBP
60
0.0
0.5
0.8
1.2
ng/ml
2.0
3.2
5.0
MTD
Hemodynamic Response
(Single Patient)
120
HR
DP08
100
80
60
40
200
180
160
140
120
100
80
60
40
30
25
20
15
10
5
SBP
ICP
Effect on Blood Pressure
Propofol
Dexmedetomidine
175
150
Arterial
pressure
(mm Hg)
125
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
VASOCONSTRICTION
8500
8000
awake
VASODILATION
7500
7000
6500
6000
5500
anesthetized
5000
4500
4000
0.3
0.45
0.68
1.0
1.5
Clonidine Target levels (ng/ml)
Time (min)
2.25
Dexmedetomidine/
%
35
30
25
20
15
10
5
0
-5
-10
DEXMEDETOMIDINE
General anesthesia
%
35
30
LTF
25
20
15
10
5
0
-5
105 -10
SBP
100
95
90
85
0.075
0.15
0.3
0.60 80
Dexmedetomidine Levels (ng/ml)
75
Time (min)
SALINE
LTF
105
100
95
90
85
80
75
SBP
Time (min)
Dexmedetomidine/
%
60
Percent Change in LTF data
40
VASOCONSTRICTION
20
VASODILATION
BLOCKED ARM
0
UNBLOCKED ARM
-20
-40
0.075
0.15
0.3
0.6
Dexmedetomidine Levels (ng/ml)
-60
Time (min)
mmHg
140
130
120
110
100
bpm 90
80
70
60
50
40
Axillary block
SBP
HR
0.075
0.15
0.3
Time (min)
0.6
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
120
0.5*
0.8*
1.25*
2.0*
3.2*
5.0*
8.0*
PaCO2
100
mm Hg
80
†
†
2.0*
3.2*
†
†
†
1.25*
2.0*
3.2*
†
60
40
20
0
Baseline
0.5*
0.8*
1.25*
Respiratory Rate
30
25
20
breaths/min 15
10
5
0
Baseline
0.5*
0.8*
Data are mean ± SEM.
*Target dexmedetomidine (ng/mL).
†P<0.05 compared with baseline values.
Adapted from Ebert et al. Anesthesiology. 2000;93:389.
5.0*
5.0*
8.0*
8.0*
Respiratory Response
MTD
50
45
CO2
40
25
20
RR
15
10
0.0
0.5
0.8
1.2
ng/ml
2.0
3.2
5.0
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
X
?
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