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CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE

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. HISTORICAL PERSPECTIVES OF NEUROMUSCULAR BLOCKING AGENTS.

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CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE

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  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’s Alcuronium 1970’s Pancuronium bromide, Fazadinium 1980’s Vecuronium bromide, Atracurium besylate 1990 Pipecuronium bromide 1991 Doxacurium chloride 1992 Mivacurium chloride 1994 Rocuronium bromide 1999 Rapacuronium 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 ED95) • Potency (number of molecules) • Keo (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 Meperidine 1 mg/kg Atropine 0.01 mg/kg Induction Propofol to 2.5 mg/kg Alfentanil to 0.25 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 blockade 96 ± 5% Mean time to 80% blockade 117 ± 24 seconds Mean time to maximum blockade 214 ± 25 seconds Mean time to completion of intubation 159 ± 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 BROMIDERAPID SEQUENCE INTUBATION

  15. ROCURONIUM BROMIDE RAPID SEQUENCE INTUBATION 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 Dose Percentage of patients with excellent-to-good conditions Rocuronium bromide (n=120) 0.6 mg/kg 99% (95% confidence interval 95%-99.9%) Succinylcholine chloride (n=110) 1.0-1.5 mg/kg 98% (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 T1 nmin 10% of control 12 18 ± 1 25% of control 14 21 ± 1 90% of control 14 36 ± 2 Spontaneous Recoverynmin T 10-25 12 4 ± 1 T 25-75 14 9 ± 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 Significant Insignificant 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. 100 600 mcg/kg 900 mcg/kg 1200 mcg/kg 90 80 Heart Rate (beats/min) 70 60 50 40 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Time (minutes) Effects of Rocuronium on Heart Rate Levy et al. Anesth Analg 1994;78,318-321.

  25. 600 mcg/kg 900 mcg/kg 1200 mcg/kg 100 90 Effects of Rocuronium on Mean Arterial Pressure 80 Mean Arterial Pressure (mmHg) 70 60 50 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Time (minutes) Levy et al. Anesth Analg 1994;78,318-321.

  26. 600 mcg/kg 900 mcg/kg 1200 mcg/kg 3.0 2.5 Effects of Rocuronium on Histamine Release 2.0 Plasma Histamine (ng/ml) 1.5 1.0 0.5 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Time (minutes) Levy et al. Anesth Analg 1994;78,318-321.

  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 N2O/HALOTHANE ANESTHESIA

  30. ONSET AND DURATION OF ACTION OF ROCURONIUM BROMIDE IN CHILDREN (1-5 YRS.) DURING N2O/HALOTHANE ANESTHESIA

  31. PHARMACODYNAMICS OF ROCURONIUM BROMIDE IN GERIATRICS

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

  33. ROCURONIUM BROMIDE: INFLUENCE OF AGESummary 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 AGESummary 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 AGESummary 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 AGESummary 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 Onsetof Neuromuscular BlockageUnder Steady State Isoflurane Anesthesia Normal Renal Function* Renal Transplantation*† (n = 10) (n = 10) Onset Time (sec) 69 ± 24 63 ± 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 BROMIDEIN HEPATIC DISEASE

  40. ROCURONIUM BROMIDEEffects 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 BROMIDEEffects 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 BROMIDEContinuous 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 BROMIDEContinuous 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

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