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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

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  1. Alpha-2 Adrenergic Agonists (dexmedetomidine)Pekka Talke MDUCSF Faculty Development LectureJan 2004

  2. 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

  3. 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

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

  5. 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)

  6. Norepinephrine Epinephrine Dopamine Tizanidine Clonidine MPV-2426 Mivazerol Guanfacine Guanabenz Medetomidine Dexmedetomidine Alpha-Adrenoceptor Agonists Alpha 1 Alpha 2

  7. H Cl N N Clonidine N Cl H CH3 Dexmedetomidine N CH3 N CH3 Alpha-2 Agonists

  8. 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) 2 Agonists

  9. Outline • Overview of Alpha-2 adrenoceptors and agonists • Selected clinical effects • Sedation • Hemodynamics • Ventilation • Other effects mediated by alpha-2 agonists • Practical points (Dosing)

  10. Sedation • Dose dependent • Minimal respiratory depression • Arousable • Known action • Hyperpolarization of LC neurons –a2A-receptor subtype • Resembles natural sleep (ICU?) • Reversible (atipamezole) • Amnesia?

  11. 25 20 OAA/S 15 § 10 5 Plasma Dexmedetomidine (ng/ml) Sedation ScoresMaximum Tolerable Dose Study § §Significant change in variable during dexmedetomidine infusions. Adapted from Ebert et al. Anesthesiology. 2000;93:389.

  12. Arousability From SedationDuring Dexmedetomidine Infusion Low Placebo Moderate 110 100 90 BIS 80 70 60 50 pre 10 20 30 40 50 60 tests 0.5 1 tests 1.5 2 3 4 tests Infusion Period (min) Recovery Period (hr) Hall. Anesth Analg. 2000;90:701.

  13. 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.

  14. Comparison of Equi-Sedative Doses of Midazolam and Dexmedetomidine on Task Performance in Humans 110 100 90 Task and noise % Hits 80 Task alone 70 60 50 Placebo Dex Midazolam Drug

  15. 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)

  16. 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)

  17. 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.

  18. 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.

  19. Outline • Overview of alpha-2 adrenoceptors and agonists • Physiologic effects mediated by alpha-2 agonists • Selected clinical effects • Sedation • Hemodynamics • Ventilation • Practical points (Dosing)

  20. 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

  21. 90 80 70 60 50 40 Time Heart Rate Response beats/min

  22. 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.

  23. 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)

  24. 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.

  25. Heart rate Response MTD ng/ml

  26. Hemodynamic Response (Single Patient) HR SBP ICP

  27. Effect on Heart Rate Propofol 130 Dexmedetomidine 120 110 100 Heart Rate (beats min-1) 90 80 70 60 50 +16 +24 +4 +12 +20 +8 0 1 2 3 8 4 5 6 7 Time (hr) Infusion Sedative drug discontinued Venn RM, Grounds RM. Br J Anaesth. 2001;87:684-690.

  28. 100 95 90 85 80 75 70 65 60 Time Blood Pressure Response MAP mm Hg

  29. Hemodynamic Response MTD ng/ml

  30. Hemodynamic Response (Single Patient) HR SBP ICP

  31. 175 150 125 100 75 50 0 1 2 3 4 5 6 7 8 +4 +8 +12 +16 +20 +24 Effect on Blood Pressure Propofol Dexmedetomidine Arterial pressure (mm Hg) Infusion Time (hr) Sedative drug discontinued Venn RM, Grounds RM. Br J Anaesth. 2001;87:684-690.

  32. 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

  33. Clonidine/ General anesthesia

  34. Dexmedetomidine/ General anesthesia

  35. Dexmedetomidine/ Axillary block

  36. 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.

  37. Outline • Overview of Alpha-2 adrenoceptors and agonists • Selected clinical effects • Sedation • Hemodynamics • Ventilation • Other effects mediated by alpha-2 agonists • Practical points (Dosing)

  38. 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

  39. PaO2 mm Hg PaCO2 † † mm Hg † Respiratory ResponseMaximum Tolerable Dose Study Respiratory Rate † † † breaths/min Data are mean ± SEM. *Target dexmedetomidine (ng/mL). †P<0.05 compared with baseline values. Adapted from Ebert et al. Anesthesiology. 2000;93:389.

  40. Respiratory Response MTD ng/ml

  41. Outline • Overview of Alpha-2 adrenoceptors and agonists • Selected clinical effects • Sedation • Hemodynamics • Ventilation • Other effects mediated by alpha-2 agonists • Practical points (Dosing)

  42. Alpha-2 AR Mediated Responses • Numerous alpha-2 AR mediated responses • Different dose response curve for each

  43. 2-Receptor Subtypes Physiology of 2 Andrenoceptors a2A Anxiolysis a2A a2C X ? a2B a2B a2A X ? a2B a2A

  44. 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

  45. Effects of Alpha-2 Agonists • No effect on ICP • Reduces IOP • No effect on relaxants • Prolongs local anesthetic action • Decreases metabolism • Decreases oxygen consumption

  46. 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?

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

  48. 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

  49. Patient Selection • High sympathetic activity • Agitated/anxious • With discomfort NOT • Low blood pressure • Hypovolemic/shock • Conduction defects

  50. 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

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