Alpha-2 Adrenergic Agonists (dexmedetomidine) Pekka Talke MD
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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 N N Cl H CH3 N CH3 CH3 Clonidine N Dexmedetomidine
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.
65 60 55 50 HR 4 5 6 5 CO 4 30.0 0.5 0.8 1.2 2. 3. 5 Heart rate Response MTD ng/ml
120 D 100 80 60 40 200 180 160 140 120 100 80 60 40 30 25 20 15 1 0 5 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
250 225 200 175 SVR 150 125 100 80 SBP 60 0.0 0.5 0.8 1.2 2. 3. 5 Hemodynamic Response MTD ng/ml
120 D 100 80 60 40 200 180 160 140 120 100 80 60 40 30 25 20 15 1 0 5 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-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/ General anesthesia % 35 30 25 20 15 10 5 0 -5 -10 DEXMEDETOMIDINE % 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/ Axillary block % 60 Percent Change in LTF data 40 VASOCONSTRICTION 20 VASODILATION BLOCKED ARM 0 UNBLOCKED ARM -20 -40 -60 0.075 0.15 0.3 0.6 Dexmedetomidine Levels (ng/ml) Time (min) mmHg 140 130 120 110 100 bpm 90 80 70 60 50 40 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*
50 CO2 45 40 25 20 RR 15 10 0.0 0.5 0.8 1.2 2. 3. 5 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 2A Anxiolysis 2A ? 2C X 2B 2B 2A X ? 2B 2A
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
