1. Alpha-2 Adrenergic Agonists (dexmedetomidine) Pekka Talke MD UCSF Faculty Development Lecture Jan 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. Alpha-Adrenoceptor Agonists Norepinephrine Epinephrine Dopamine Tizanidine Clonidine MPV-2426 Mivazerol Guanfacine Guanabenz Medetomidine Dexmedetomidine Alpha 2 Alpha 1

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

8.  2 Agonists Clonidine Selectivity:  2 :  1 250:1 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) Dexmedetomidine Selectivity:  2 :  1 1620:1 Imidazole derivate 31:1 t 1/2  2 hrs V ss 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)

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 –  2 A-receptor subtype Resembles natural sleep (ICU?) Reversible (atipamezole) Amnesia?

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

12. 50 60 70 80 90 100 110 pre102030405060tests0.51tests1.5234tests Moderate Low Placebo Infusion Period (min)Recovery Period (hr) BIS Hall. Anesth Analg. 2000;90:701. Arousability From Sedation During Dexmedetomidine Infusion

13. 40 60 80 100 BIS Placebo0.20.6 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 Dexmedetomidine Infusion

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

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. 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) ICP SBP HR

27. Effect on Heart Rate 130 120 110 100 90 80 70 60 50 +24 +20 +16 +12 +8 +4 0123 4567 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.

28. Blood Pressure Response MAP mm Hg

29. Hemodynamic Response MTD ng/ml

30. Hemodynamic Response (Single Patient) ICP SBP HR

31. Effect on Blood Pressure Sedative drug discontinued Arterial pressure (mm Hg) 012345678+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.

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, V E, Pa CO 2, –Small decrease in V E /ET CO 2 No potentiation of opioid-induced respiratory depression Sedation: upper airway obstruction Irregular RR with large boluses

39. Respiratory Response Maximum 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. mm Hg PaO 2 † † † Respiratory Rate mm Hg PaCO 2 † †† breaths/min

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 2A2A ? ? 2A2A 2C2C 2A2A 2A2A Anxiolysis 2B2B 2B2B X 2B2B X Physiology of  2 Andrenoceptors

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

51. 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

52. 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

53. 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