Alpha2 Adrenergic Agonists dexmedetomidine Pekka Talke MD UCSF

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

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 –

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 –

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

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

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

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

Alpha-Adrenoceptor Agonists Alpha 1 Alpha 2 • • • Norepinephrine Epinephrine Dopamine Tizanidine Clonidine

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 CH 3 Clonidine N Dexmedetomidine N Cl H N

Alpha-2 Agonists H Cl N CH 3 Clonidine N Dexmedetomidine N Cl H N CH 3 N

 2 Agonists Clonidine Dexmedetomidine • Selectivity: 2: 1 250: 1 • Selectivity: 2:

2 Agonists Clonidine Dexmedetomidine • Selectivity: 2: 1 250: 1 • Selectivity: 2: 1 1620: 1 • Imidazole derivate 16: 1 • • • t 1/2 10 hrs • 2. 5 L/kg • PO, patch, epidural • Antihypertensive • Epidural formulation Duraclon 1, 000 ug/vial, IV ($50) Imidazole derivate 31: 1 t 1/2 2 hrs Vss 118 L (gets everywhere) 94% protein bound Eliminated by liver/kidney Effects own PK (V 1? CO? ) Sedative Only available in IV form Precedex 200 ug/vial ($55)

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

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

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

Sedation Scores Maximum Tolerable Dose Study 25 20 OAA/S 15 § 10 5 §

Sedation Scores Maximum Tolerable Dose Study 25 20 OAA/S 15 § 10 5 § §Significant change in variable during dexmedetomidine infusions. Adapted from Ebert et al. Anesthesiology. 2000; 93: 389. Plasma Dexmedetomidine (ng/ml)

Arousability From Sedation During Dexmedetomidine Infusion Placebo 110 Low Moderate 100 90 BIS 80

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

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

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%

Anesthesia/Analgesia Sparing • Intraop, postop • Induction agents, inhalation anesthetics, opioids, midazolam • 40% with dexmedetomidine (0. 6 -0. 8 ng/m. L), 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

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. •

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.

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

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

Hemodynamic effects • Combination of effects mediated by: – Reduction of central SNS activity (alpha-2 a) – Reduction of presynaptic NE release (alpha-2 a and c) – Stimulation of VSM cells (alpha-2 b) – Stimulation of endothelium – Stimulation of central imidazoline receptors – Some vagomimetic activity

Heart Rate Response 90 80 70 beats/min 60 50 40 Time

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

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.

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

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 ng/ml

Heart rate Response MTD ng/ml

Hemodynamic Response (Single Patient) HR SBP ICP

Hemodynamic Response (Single Patient) HR SBP ICP

Effect on Heart Rate Propofol Dexmedetomidine 130 120 110 100 Heart Rate (beats min-1)

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 Sedative drug discontinued Venn RM, Grounds RM. Br J Anaesth. 2001; 87: 684 -690. Time (hr)

Blood Pressure Response 100 95 90 85 MAP mm Hg 80 75 70 65

Blood Pressure Response 100 95 90 85 MAP mm Hg 80 75 70 65 60 Time

Hemodynamic Response MTD ng/ml

Hemodynamic Response MTD ng/ml

Hemodynamic Response (Single Patient) HR SBP ICP

Hemodynamic Response (Single Patient) HR SBP ICP

Effect on Blood Pressure Propofol Dexmedetomidine 175 150 Arterial pressure (mm Hg) 125 100

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 Venn RM, Grounds RM. Br J Anaesth. 2001; 87: 684 -690. Sedative drug discontinued Time (hr)

Alpha-2 b / Vasoconstriction • Alpha-2 b adrenoceptors at vascular smooth muscle cells mediate

Alpha-2 b / Vasoconstriction • Alpha-2 b 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

Clonidine/ General anesthesia

Dexmedetomidine/ General anesthesia

Dexmedetomidine/ General anesthesia

Dexmedetomidine/ Axillary block

Dexmedetomidine/ Axillary block

Common observation • BP increased when I gave dex, What should I do? •

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

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

Effect on Ventilation (Alpha-2) • Clonidine, dexmedetomidine – Minimal effect on RR, VE, Pa CO 2, – Small decrease in VE/ET CO 2 • No potentiation of opioid-induced respiratory depression • Sedation: upper airway obstruction • Irregular RR with large boluses

Respiratory Response Maximum Tolerable Dose Study Pa. O 2 mm Hg Pa. CO 2

Respiratory Response Maximum Tolerable Dose Study Pa. O 2 mm Hg Pa. CO 2 mm Hg † † Respiratory Rate † breaths/min Data are mean ± SEM. *Target dexmedetomidine (ng/m. L). †P<0. 05 compared with baseline values. Adapted from Ebert et al. Anesthesiology. 2000; 93: 389. † † †

Respiratory Response MTD ng/ml

Respiratory Response MTD ng/ml

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

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

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 2 A ?

2 -Receptor Subtypes Physiology of 2 Andrenoceptors 2 A Anxiolysis 2 A ? 2 C X 2 B 2 A X ? 2 B 2 A

Effects of Alpha-2 Agonists – Endocrine • • NE release insulin release cortisol release

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

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 –

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

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

Outline • Overview of alpha-2 adrenoceptors and alpha-2 agonists • Selected clinical effects –

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

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 –

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

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)

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 –

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