1. CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Division of Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia

2. HISTORICAL PERSPECTIVES OF NEUROMUSCULAR BLOCKING AGENTS

3. INTRODUCTION OF NEW DRUGS 1494 - 1942 Curare 1947 - 1951 Succinylcholine chloride, Gallamine, Metocurine, Decamethonium 1960’sAlcuronium 1970’sPancuronium bromide, Fazadinium 1980’sVecuronium bromide, Atracurium besylate 1990Pipecuronium bromide 1991Doxacurium chloride 1992Mivacurium chloride 1994Rocuronium bromide 1999Rapacuronium bromide

4. STRUCTURAL CLASSES OF NONDEPOL.ARIZING RELAXANTS Steroids: Rocuronium bromide, Vecuronium bromide, Pancuronium bromide, Pipecuronium bromide Naturally occurring benzylisoquinolones: curare, metocurine Benzylisoquinoliniums: Atracurium besylate, Mivacurium chloride, Doxacurium chloride

5. THE IDEAL RELAXANT Nondepolarizing Rapid onset Dose-dependent duration No side-effects Elimination independent of organ function No active or toxic metabolites

6. ONSET OF PARALYSIS IS AFFECTED BY: Dose (relative to ED 95 ) Potency (number of molecules) K eo (chemistry/blood flow) Clearance Age

7. PHARMACODYNAMICS OF ROCURONIUM BROMIDE

8. ONSET OF ROCURONIUM BROMIDE Onset: rapid to intermediate (dose dependent)

9. TRACHEAL INTUBATION Pre-Medication Meperidine1 mg/kg Atropine0.01 mg/kg Induction Propofol to2.5 mg/kg Alfentanil to0.25 mg/kg Rocuronium bromide 0.6 mg/kg OR Succinylcholine chloride 1 mg/kg Intubation 60 sec. later

10. ROCURONIUM BROMIDE: TRACHEAL INTUBATION Median time to  80% block with 0.6 mg/kg is 60 seconds (0.4-6.0 minutes) Median onset time with 0.6 mg/kg is 1.8 minutes (0.6-13 minutes)

11. ROCURONIUM BROMIDE: TRACHEAL INTUBATION Median time to  80% blockade with 0.45 mg/kg is 78 seconds (0.8-6.2 minutes) Median onset time with 0.45 mg/kg is 3.0 minutes (1.3-8.2 minutes)

12. LOW DOSE PHARMACODYNAMICS: CLINICAL PARAMETERS Rocuronium bromide Dose:.45 mg/kg (n = 14) Mean maximum blockade96 ± 5% Mean time to 80% blockade117 ± 24 seconds Mean time to maximum blockade214 ± 25 seconds Mean time to completion of intubation159 ± 25 seconds

13. ROCURONIUM BROMIDE: TRACHEAL INTUBATION Median time to  80% blockade with 0.9 mg/kg is 66 seconds (0.3-3.8 minutes) Median onset time with 0.9 mg/kg is 84 seconds (0.8-6.2 minutes) Median time to  80% blockade with 1.2 mg/kg is 42 seconds (0.4-1.7 minutes) Median onset time with 1.2 mg/kg is 60 seconds (0.6-4.7 minutes)

14. ROCURONIUM BROMIDE RAPID SEQUENCE INTUBATION

15. n = 230 (six clinical trials) Premedication:midazolam or temazepam Induction:thiopental (3-6 mg/kg) fentanyl (2-5 mcg/kg) or+or propofol (1.5 - 2.5 mg/kg) alfentanil (1 mg) Rocuronium bromide dose:0.6 mg/kg Succinylcholine chloride dose:1-1.5 mg/kg

16. RAPID SEQUENCE INTUBATION Rapid sequence intubation: excellent-to-good conditions achieved within 60 - 90 seconds of administration in most patients DosePercentage of patients with excellent-to-good conditions Rocuronium bromide (n=120)0.6 mg/kg99% (95% confidence interval 95%-99.9%) Succinylcholine chloride (n=110)1.0-1.5 mg/kg98% (95% confidence interval 95%-99.8%)

17. DURATION OF ACTION OF NEUROMUSCULAR BLOCKING AGENTS Ultra-Short: Succinylcholine chloride Short: Mivacurium chloride Intermediate: Rocuronium bromide, Vecuronium bromide, Atracurium besylate Long: Pancuronium bromide, curare, metocurine, Pipecuronium bromide, Doxacurium chloride

18. LOW DOSE PHARMACODYNAMICS: DURATION Rocuronium bromide Dose:.45 mg/kg From injection to Recovery of T 1 nmin 10% of control1218 ± 1 25% of control1421 ± 1 90% of control1436 ± 2 Spontaneous Recoverynmin T 10-25124 ± 1 T 25-75149 ± 1 Adapted from: Tullock et al Anesthesiology, vol 75, no. 3A, 1991

19. CARDIOVASCULAR PROFILE OF ROCURONIUM BROMIDE AND OTHER NEUROMUSCULAR BLOCKING AGENTS

20. HISTAMINE RELEASING POTENTIAL SignificantInsignificant Tubocurarine+ + +Rocuronium bromide ± Metocurine++Vecuronium bromide ± Atracurium besylate+Pancuronium bromide ± Mivacurium chloride+Pipecuronium bromide ± Succinylcholine chloride+Doxacurium chloride ±

21. Muscle Relaxants Pancuronium Vagolytic: increases heart rate, may require beta blockade Easy to use Intermediate duration of action Slower onset Not reversed at end of case

22. Muscle Relaxants Vecuronium No effects on HR, BP Requires reconstitution Reliable and controllable duration of action Slower onset Stable hemodynamics/no histamine release

23. Muscle Relaxants Rapacuronium Minimal effects on HR, BP Controllable duration of action Fast onset Stable hemodynamics/minimal histamine release Potential for bronchospasm led to its removal in 2001

24. Effects of Rocuronium on Heart Rate Time (minutes) 10090 80 70 60 50 40 0.01.02.03.04.05.06.0 Heart Rate (beats/min) Levy et al. Anesth Analg 1994;78,318-321. 600 mcg/kg 900 mcg/kg 1200 mcg/kg

25. Effects of Rocuronium on Mean Arterial Pressure Time (minutes) 100 90 80 70 60 50 0.01.02.03.04.05.06.0 Mean Arterial Pressure (mmHg) 600 mcg/kg 900 mcg/kg 1200 mcg/kg Levy et al. Anesth Analg 1994;78,318-321.

26. Effects of Rocuronium on Histamine Release Time (minutes) 0.01.02.03.04.05.0 Plasma Histamine (ng/ml) Levy et al. Anesth Analg 1994;78,318-321. 600 mcg/kg 900 mcg/kg 1200 mcg/kg 3.0 2.5 2.0 1.5 1.0 0.5 0.0

27. ROCURONIUM BROMIDE: CARDIOVASCULAR PROFILE Favorable cardiovascular profile Histamine release unlikely Mild vagolytic activity

28. PHARMACODYNAMICS OF ROCURONIUM BROMIDE IN PEDIATRICS

29. ONSET AND DURATIONOF ACTION OF ROCURONIUM BROMIDE IN INFANTS (3 MOS.-1 YR. DURING N 2 O/HALOTHANE ANESTHESIA

30. ONSET AND DURATION OF ACTION OF ROCURONIUM BROMIDE IN CHILDREN (1-5 YRS.) DURING N 2 O/HALOTHANE ANESTHESIA

31. PHARMACODYNAMICS OF ROCURONIUM BROMIDE IN GERIATRICS

32. ROCURONIUM BROMIDE IN THE ELDERLY (>65YR.)

33. ROCURONIUM BROMIDE: INFLUENCE OF AGE Summary Pediatrics (3 mos. - 1 yr): 0.6 mg/kg Rocuronium bromide produces excellent to good intubating conditions within 1 minute, with 41 minutes of clinical relaxation (median) Rocuronium bromide package insert

34. ROCURONIUM BROMIDE: INFLUENCE OF AGE Summary Pediatrics (1 yr - 12 yrs): 0.6 mg/kg Rocuronium bromide produces excellent to good intubating conditions within 1 minute, with 27 minutes of clinical relaxation (median) Rocuronium bromide package insert

35. ROCURONIUM BROMIDE: INFLUENCE OF AGE Summary Adults (18 - 64 yrs): 0.6 mg/kg Rocuronium bromide produces excellent to good intubating conditions within 60 seconds, with 31 minutes of clinical relaxation (median) Rocuronium bromide package insert

36. ROCURONIUM BROMIDE: INFLUENCE OF AGE Summary Geriatric (  65 yrs): 0.6 mg/kg Rocuronium bromide produces excellent to good intubating conditions within 2.3 minutes, with 46 minutes of clinical relaxation (median) Rocuronium bromide package insert

37. CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE IN RENAL FAILURE

38. Rocuronium bromide (0.6 mg/kg) Effects of Renal Failure on Onset of Neuromuscular Blockage Under Steady State Isoflurane Anesthesia Normal Renal Function*Renal Transplantation* †(n = 10) Onset Time (sec)69 ± 2463 ± 17 * Values are mean ± SD † Patients with end-stage renal disease undergoing cadaver renal transplantation Adapted from: Szenochradsky et al Anesthesiology 77;899-904, 1992

39. CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE IN HEPATIC DISEASE

40. ROCURONIUM BROMIDE Effects of Hepatic Disease Under Steady State Isoflurane Anesthesia Neuromuscular Effects Onset unchanged Recovery increased Larger or repeat doses may have prolonged effect Rocuronium bromide package insert

41. ROCURONIUM BROMIDE Effects of Hepatic Disease Under Steady State Isoflurane Anesthesia Pharmacokinetics Clearance unchanged Central and steady state distribution volumes and elimination half-life increased Rocuronium bromide package insert

42. THE PHARMACODYNAMICS OF ROCURONIUM BROMIDE IN THE OBESE

43. Obesity defined as  30% of Ideal Body Weight Dose can be based on patient’s actual body weight Rocuronium bromide package insert

44. ROCURONIUM BROMIDE IN CONTINUOUS INFUSION

45. ROCURONIUM BROMIDE Continuous Infusion Recommended Initial Infusion Rate (Adult): 0.01-0.012 mg/kg/min. initiated only after spontaneous recovery from an intubating dose Upon reaching the desired level of neuromuscular block, the infusion of Rocuronium bromide must be individualized for each patient Rocuronium bromide package insert

46. ROCURONIUM BROMIDE Continuous Infusion Recommended Initial Infusion Rate (Pediatric): 0.012 mg/kg/min. initiated only after spontaneous recovery from an intubating dose (under Halothane) Upon reaching the desired level of neuromuscular block, the infusion of Rocuronium bromide must be individualized for each patient Rocuronium bromide package insert

47. ROCURONIUM BROMIDE DRUG INTERACTIONS

48. ROCURONIUM BROMIDE: DRUG INTERACTIONS Intravenous Anesthetics: The use of propofol for Induction and maintenance of anesthesia does not alter clinical duration of recovery Rocuronium bromide package insert

49. ROCURONIUM BROMIDE: DRUG INTERACTIONS Volatile Anesthetics: Rocuronium bromide requirements are reduced by approximately 10-25% when used with enflurane or isoflurane, but little change when used with halothane Rocuronium bromide package insert

50. ROCURONIUM BROMIDE: DRUG INTERACTIONS Antibiotics: Drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as Rocuronium bromide include certain antibiotics (i.e., aminoglycosides; vancomycin; tetracyclines; bacitracin; polymyzins; collistin; and sodium colistimethate) Rocuronium bromide package insert

51. ROCURONIUM BROMIDE: DRUG INTERACTIONS Anticonvulsants: shorter durations of neuromuscular block may occur and infusion rates may be higher Rocuronium bromide package insert

52. ROCURONIUM BROMIDE CONCLUSIONS Mono-quaternary steroidal drug Structural relative of Vecuronium bromide Rapid to intermediate onset of action. Significantly more rapid than Vecuronium bromide or Atracurium besylate For use in outpatient or inpatient procedures of varying lengths suitable for rapid sequence intubation Favorable cardiovascular profiles Eliminated mainly by liver: minimally by the kidneys

53. Current Concepts in Neuromuscular Blockade 7776

54. Neuromuscular Agents: Costs of Care Cost of care  acquisition cost The real, substantial savings accrue from use of intermediate- and short-acting drugs because: Inexpensive, long-acting drugs are associated with prolonged postoperative recovery 1 Fast recovery means shorter risk periods of residual blockade. This translates into fewer postoperative complications, as shown in the Berg study 2 Postoperative complications are very expensive Avoiding these is where the real cost savings accrue 1 Ballantyne JC, et al. Anesth Analg. 1997; 85:476 2 Berg H, et al. Acta Anaesthesiol Scand. 1997;41:1095

55. Cardiovascular stability Nondepolarizing vs depolarizing Organ-independent elimination Clinically significant active or toxic metabolites Predictability of duration Cumulative effects Reversibility Time to onset Stability of solution Cost Rationale for Selection of NMBs: