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Alpha-2 Adrenergic Agonists Alpha-2 Adrenergic Agonists (dexmedetomidine)(dexmedetomidine)
Pekka Talke MDPekka Talke MDUCSF Faculty Development UCSF Faculty Development
LectureLectureJan 2004Jan 2004
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OutlineOutline
• 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
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OutlineOutline
• 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
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Nine AdrenoceptorsNine Adrenoceptors
• Alpha-1a, Alpha-1b and Alpha-1d • Beta-1, Beta-2, Beta-3• Alpha-2a, Alpha-2b and Alpha-2c
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AdrenoceptorsAdrenoceptors
• 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)
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Alpha-Adrenoceptor AgonistsAlpha-Adrenoceptor Agonists
• Norepinephrine• Epinephrine• Dopamine• Tizanidine• Clonidine• MPV-2426• Mivazerol• Guanfacine• Guanabenz• Medetomidine• DexmedetomidineAlpha 2
Alpha 1
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Alpha-2 AgonistsAlpha-2 Agonists
N
N
H
N
Cl
Cl
Clonidine
CH3
CH3
N
N
CH3H
Dexmedetomidine
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2 2 AgonistsAgonists
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)
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OutlineOutline
• Overview of Alpha-2 adrenoceptors and agonists• Selected clinical effects
– Sedation– Hemodynamics– Ventilation
• Other effects mediated by alpha-2 agonists • Practical points (Dosing)
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SedationSedation
• Dose dependent• Minimal respiratory depression• Arousable• Known action
– Hyperpolarization of LC neurons– 2A-receptor subtype
• Resembles natural sleep (ICU?)• Reversible (atipamezole)• Amnesia?
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Sedation ScoresSedation Scores Maximum Tolerable Dose StudyMaximum Tolerable Dose Study
5
10
15
20
25
OAA/S
§
Plasma Dexmedetomidine (ng/ml)
0
25
50
75
100
Baseline 0.7 1.2 1.9 3.2 5.1 8.4 14.7
VAS
§
§Significant change in variable during dexmedetomidine infusions.Adapted from Ebert et al. Anesthesiology. 2000;93:389.
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50
60
70
80
90
100
110
pre 10 20 30 40 50 60 tests 0.5 1 tests 1.5 2 3 4 tests
ModerateLowPlacebo
Infusion Period (min) Recovery Period (hr)
BIS
Hall. Anesth Analg. 2000;90:701.
Arousability From SedationArousability From SedationDuring Dexmedetomidine During Dexmedetomidine
InfusionInfusion
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40
60
80
100
BIS
Placebo 0.2 0.6
During cognitive and cold pressor testing
Just prior to cognitive and cold pressor testing
Dexmedetomidine Infusion (µg/kg-1/hr-1)
Hall. Anesth Analg. 2000;90:701.
Arousability From Sedation During Arousability From Sedation During Dexmedetomidine InfusionDexmedetomidine Infusion
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Comparison of Equi-Sedative Doses of Comparison of Equi-Sedative Doses of Midazolam and Dexmedetomidine on Midazolam and Dexmedetomidine on
Task Performance in HumansTask Performance in Humans
50
60
70
80
90
100
110
Placebo Dex Midazolam
Drug
% H
its
Task and noiseTask alone
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Anesthesia/Analgesia SparingAnesthesia/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)
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SedationSedation
• 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)
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SedationSedation
• 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.
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SedationSedation
• 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.
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OutlineOutline
• Overview of alpha-2 adrenoceptors and agonists• Physiologic effects mediated by alpha-2 agonists• Selected clinical effects
– Sedation– Hemodynamics– Ventilation
• Practical points (Dosing)
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Hemodynamic effectsHemodynamic 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
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Heart Rate ResponseHeart Rate Response
beats/min
40
50
60
70
80
90
Time
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HR effectsHR 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.
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HR effectsHR 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)
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HR effectsHR 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.
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COHR345645505560650.00.50.81.22.03.25.0
Heart rate Response Heart rate Response MTDMTD
ng/ml
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Hemodynamic Response Hemodynamic Response (Single Patient)(Single Patient) DP08406080100120
40608010012014016018020051015202530ICP
SBP
HR
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Effect on Effect on Heart RateHeart Rate
130
120
110
100
90
80
70
60
50+24+20+16+12+8+40 1 2 3 4 5 6 7 8
Heart Rate (beats min-1)
Time (hr)Sedative drug discontinued
Propofol
Dexmedetomidine
Infusion
Venn RM, Grounds RM. Br J Anaesth. 2001;87:684-690.
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Blood Pressure ResponseBlood Pressure Response
MAPmm Hg
60
65
70
75
80
85
90
95
100
Time
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SBPSVR608010010001250150017502000225025000.00.50.81.22.03.25.0
Hemodynamic Response Hemodynamic Response MTDMTD
ng/ml
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Hemodynamic Response Hemodynamic Response (Single Patient)(Single Patient) DP08406080100120
40608010012014016018020051015202530ICP
SBP
HR
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Effect on Effect on Blood Pressure Blood Pressure
Sedative drugdiscontinued
Arterial pressure (mm Hg)
0 1 2 3 4 5 6 7 8 +4 +8 +12 +16 +20 +24
50
75
100
125
150
175
Time (hr)
Propofol
Dexmedetomidine
Infusion
Venn RM, Grounds RM. Br J Anaesth. 2001;87:684-690.
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Alpha-2b / VasoconstrictionAlpha-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
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Clonidine/ General anesthesiaClonidine/ General anesthesia
4000
4500
5000
5500
6000
6500
7000
7500
8000
8500
9000
4000
4500
5000
5500
6000
6500
7000
7500
8000
8500
9000nA
Time (min)
Clonidine Target levels (ng/ml)
0.3 0.45 0.68 1.0 1.5 2.25
anesthetized
awake
VASOCONSTRICTION
VASODILATION
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Dexmedetomidine/ Dexmedetomidine/ General General anesthesiaanesthesia
-10-505
101520253035
-10-505
101520253035
%
LTF
7580859095100105
7580859095100105
DEXMEDETOMIDINE
-10-505
101520253035
-10-505
101520253035
7580859095100105
7580859095100105
SBP
SALINE
Time (min)
0.075 0.15 0.3 0.60
LTF
SBP
%
Dexmedetomidine Levels (ng/ml)
Time (min)
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Dexmedetomidine/ Dexmedetomidine/ Axillary blockAxillary block
-60
-40
-20
0
20
40
60
-60
-40
-20
0
20
40
60
405060708090
100110120130140
405060708090
100110120130140
%
Time (min)
0.075 0.15 0.3 0.6
HR
SBP
mmHg
Dexmedetomidine Levels (ng/ml)
bpm
Time (min)
BLOCKED ARM
VASOCONSTRICTION
VASODILATION
UNBLOCKED ARM
Percent Change in LTF data
0.075 0.15 0.3 0.6
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Common observationCommon 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.
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OutlineOutline
• Overview of Alpha-2 adrenoceptors and agonists• Selected clinical effects
– Sedation– Hemodynamics– Ventilation
• Other effects mediated by alpha-2 agonists • Practical points (Dosing)
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Effect on Ventilation (Alpha-2)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
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Respiratory ResponseRespiratory Response Maximum Tolerable Dose StudyMaximum Tolerable Dose Study
Data are mean ± SEM.*Target dexmedetomidine (ng/mL).†P<0.05 compared with baseline values.Adapted from Ebert et al. Anesthesiology. 2000;93:389.
0
20
40
60
80
100
120
Baseline 0.5* 0.8* 1.25* 2.0* 3.2* 5.0* 8.0*
mm Hg
PaO2
05
1015202530
Baseline 0.5* 0.8* 1.25* 2.0* 3.2* 5.0* 8.0*
† † †Respiratory Rate
0
20
40
60
80
100
120
Baseline 0.5* 0.8* 1.25* 2.0* 3.2* 5.0* 8.0*
mm Hg
PaCO2
† † †
breaths/min
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Respiratory Response Respiratory Response MTDMTD
RRCO2101520254045500.00.50.81.22.03.25.0
ng/ml
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OutlineOutline
• Overview of Alpha-2 adrenoceptors and agonists• Selected clinical effects
– Sedation– Hemodynamics– Ventilation
• Other effects mediated by alpha-2 agonists • Practical points (Dosing)
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Alpha-2 AR Mediated Alpha-2 AR Mediated ResponsesResponses
– Numerous alpha-2 AR mediated responses
– Different dose response curve for each
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22-Receptor Subtypes-Receptor Subtypes
2A
?
?
2A
2C
2A
2AAnxiolysis
2B
2B
XX
2B
X
Physiology of Physiology of 22 Andrenoceptors Andrenoceptors
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Effects of Alpha-2 AgonistsEffects 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
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Effects of Alpha-2 AgonistsEffects of Alpha-2 Agonists
– No effect on ICP– Reduces IOP– No effect on relaxants– Prolongs local anesthetic action– Decreases metabolism– Decreases oxygen consumption
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Effects of Alpha-2 AgonistsEffects 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?
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Side EffectsSide Effects
• Sinus pause/arrest• Orthostatic hypotension• Dry mouth• Vasoconstriction
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OutlineOutline
• 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
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Patient SelectionPatient Selection
• High sympathetic activity• Agitated/anxious• With discomfort
NOT
• Low blood pressure• Hypovolemic/shock• Conduction defects
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DosingDosing
• 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
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My favourite useMy 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
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Alpha-2 agonist developmentAlpha-2 agonist development(where to look for the literature)(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
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OutlineOutline
• 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