Alpha-2 Adrenergic Agonists (dexmedetomidine) Pekka Talke MD UCSF Faculty Development Lecture Jan 2004

Alpha-2 Adrenergic Agonists Alpha-2 Adrenergic Agonists (dexmedetomidine)(dexmedetomidine)

Pekka Talke MDPekka Talke MDUCSF Faculty Development UCSF Faculty Development

LectureLectureJan 2004Jan 2004

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

OutlineOutline




Nine AdrenoceptorsNine Adrenoceptors

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

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)

Alpha-Adrenoceptor AgonistsAlpha-Adrenoceptor Agonists

• Norepinephrine• Epinephrine• Dopamine• Tizanidine• Clonidine• MPV-2426• Mivazerol• Guanfacine• Guanabenz• Medetomidine• DexmedetomidineAlpha 2

Alpha 1

Alpha-2 AgonistsAlpha-2 Agonists

N

N

H

N

Cl

Cl

Clonidine

CH3

CH3

N

N

CH3H

Dexmedetomidine

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)

OutlineOutline

• Overview of Alpha-2 adrenoceptors and agonists• Selected clinical effects

– Sedation– Hemodynamics– Ventilation

• Other effects mediated by alpha-2 agonists • Practical points (Dosing)

SedationSedation

• Dose dependent• Minimal respiratory depression• Arousable• Known action

– Hyperpolarization of LC neurons– 2A-receptor subtype

• Resembles natural sleep (ICU?)• Reversible (atipamezole)• Amnesia?

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.

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

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

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

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)

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)

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.

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.

OutlineOutline

• Overview of alpha-2 adrenoceptors and agonists• Physiologic effects mediated by alpha-2 agonists• Selected clinical effects


• Practical points (Dosing)

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

Heart Rate ResponseHeart Rate Response

beats/min

40

50

60

70

80

90

Time

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.


• 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)


• 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.

COHR345645505560650.00.50.81.22.03.25.0

Heart rate Response Heart rate Response MTDMTD

ng/ml

Hemodynamic Response Hemodynamic Response (Single Patient)(Single Patient) DP08406080100120

40608010012014016018020051015202530ICP

SBP

HR

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.

Blood Pressure ResponseBlood Pressure Response

MAPmm Hg

60

65

70

75

80

85

90

95

100

Time

SBPSVR608010010001250150017502000225025000.00.50.81.22.03.25.0

Hemodynamic Response Hemodynamic Response MTDMTD

ng/ml

Hemodynamic Response Hemodynamic Response (Single Patient)(Single Patient) DP08406080100120

40608010012014016018020051015202530ICP

SBP

HR

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.

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

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

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)

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

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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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

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

Respiratory Response Respiratory Response MTDMTD

RRCO2101520254045500.00.50.81.22.03.25.0

ng/ml

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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

22-Receptor Subtypes-Receptor Subtypes

2A

?

?

2A

2C

2A

2AAnxiolysis

2B

2B

XX

2B

X

Physiology of Physiology of 22 Andrenoceptors Andrenoceptors

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


– No effect on ICP– Reduces IOP– No effect on relaxants– Prolongs local anesthetic action– Decreases metabolism– Decreases oxygen consumption


– Dry mouth (awake fibers)– Decreases bowel motility– Decreases psychomotor performance– Not amnestic– Slows EEG – Prevents opioid induced rigidity– Neuro/cardiac protection?

Side EffectsSide Effects

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

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Patient SelectionPatient Selection

• High sympathetic activity• Agitated/anxious• With discomfort

NOT

• Low blood pressure• Hypovolemic/shock• Conduction defects

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

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

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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Documents

Alpha-2 Adrenergic Agonists (dexmedetomidine) Pekka Talke MD UCSF Faculty Development Lecture Jan 2004