Alpha2 Adrenergic Agonists dexmedetomidine Pekka Talke MD UCSF
- Slides: 53
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-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 • 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 MPV-2426 Mivazerol Guanfacine Guanabenz Medetomidine Dexmedetomidine
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: 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 – 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 – 2 A-receptor subtype • Resembles natural sleep (ICU? ) • Reversible (atipamezole) • Amnesia?
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 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/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 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-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
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 ng/ml
Hemodynamic Response (Single Patient) HR 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 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 60 Time
Hemodynamic Response MTD ng/ml
Hemodynamic Response (Single Patient) HR 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 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 vasoconstriction • Inverse relationship between arterial diameter and alpha-2 ARs. • “instantaneous” compared to the central sympatholytic effect
Clonidine/ General anesthesia
Dexmedetomidine/ General anesthesia
Dexmedetomidine/ Axillary block
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 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 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
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 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 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
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