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Home , Doxacurium chloride, Metocurine, Mivacurium chloride, Pancuronium bromide, Pipecuronium bromide, Rapacuronium bromide

CLINICAL PHARMACOLOGY OF 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 INTRODUCTION OF NEW DRUGS 1494 - 1942 1947 - 1951 Succinylcholine chloride, Gallamine, , 1960’s Alcuronium 1970’s , Fazadinium 1980’s , Atracurium besylate 1990 1991 1992 1994 Rocuronium bromide 1999 STRUCTURAL CLASSES OF NONDEPOL.ARIZING RELAXANTS

• : Rocuronium bromide, Vecuronium bromide, Pancuronium bromide, Pipecuronium bromide

• Naturally occurring benzylisoquinolones: curare, metocurine

• Benzylisoquinoliniums: Atracurium besylate, Mivacurium chloride, Doxacurium chloride THE IDEAL RELAXANT

• Nondepolarizing • Rapid onset • Dose-dependent duration • No side-effects • Elimination independent of organ function • No active or toxic metabolites ONSET OF PARALYSIS IS AFFECTED BY:

• Dose (relative to ED95) • Potency (number of molecules)

• Keo (chemistry/blood flow) • Clearance • Age OF ROCURONIUM BROMIDE ONSET OF ROCURONIUM BROMIDE

Onset: rapid to intermediate (dose dependent)

Pre- Meperidine 1 mg/kg 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 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) 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) 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 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) ROCURONIUM BROMIDE RAPID SEQUENCE INTUBATION ROCURONIUM BROMIDE RAPID SEQUENCE INTUBATION n = 230 (six clinical trials)

Premedication: or 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 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%) 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 LOW DOSE PHARMACODYNAMICS: DURATION Rocuronium bromide Dose: .45 mg/kg From injection to

Recovery of T1 n min 10% of control 12 18 ± 1 25% of control 14 21 ± 1 90% of control 14 36 ± 2

Spontaneous Recovery n min T 10-25 12 4 ± 1 T 25-75 14 9 ± 1

Adapted from: Tullock et al Anesthesiology, vol 75, no. 3A, 1991 CARDIOVASCULAR PROFILE OF ROCURONIUM BROMIDE AND OTHER NEUROMUSCULAR BLOCKING AGENTS HISTAMINE RELEASING POTENTIAL

Significant Insignificant

Tubocurarine + + + Rocuronium bromide ± Metocurine ++ Vecuronium bromide ± Atracurium besylate + Pancuronium bromide ± Mivacurium chloride + Pipecuronium bromide ± Succinylcholine chloride + Doxacurium chloride ± Muscle Relaxants

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

Vecuronium • No effects on HR, BP • Requires reconstitution • Reliable and controllable duration of action • Slower onset • Stable hemodynamics/no histamine release 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 Effects of Rocuronium on Heart Rate

100 600 mcg/kg 900 mcg/kg 90 1200 mcg/kg

80

70

60

H e a rt Rate (beats/min) RateHeart 50 40 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. Effects of Rocuronium on Mean Arterial Pressure 600 mcg/kg 100 900 mcg/kg 1200 mcg/kg 90

80

70

60

Mean50 (mmHg) 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. Effects of Rocuronium on Histamine Release

3.0

2.5 600 mcg/kg 900 mcg/kg 2.0 1200 mcg/kg 1.5

1.0

0.5 P l a sma Histamine (ng/ml) Histamine Plasma 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. ROCURONIUM BROMIDE: CARDIOVASCULAR PROFILE

• Favorable cardiovascular profile • Histamine release unlikely • Mild vagolytic activity PHARMACODYNAMICS OF ROCURONIUM BROMIDE IN PEDIATRICS ONSET AND DURATIONOF ACTION OF ROCURONIUM BROMIDE IN INFANTS

(3 MOS.-1 YR. DURING N2O/ Dose Time to Onset Clinical mg/kg 90% Block (sec) Duration (sec) (min)

Rocuronium bromide 0.6 37 ± 2 64 ± 10 41.9 ± 3.2 (20-60) (20-180) (24.3-67.7) Χ ± sem Adapted from: Woellel et al Anesthesiology 76;939, 1992 ONSET AND DURATION OF ACTION OF ROCURONIUM BROMIDE IN CHILDREN (1-5 YRS.)

DURING N2O/HALOTHANE ANESTHESIA

mg/kg Onset (Time Clinical T25-75 (min) to Max Duration (min) Block) (sec)

Rocuronium bromide 0.6 78 26.7 11.0

(Range) (42-168) (17.2-39.0) (6.0-22.8)

Adapted from: Woettel, Brandom, et al Anesthesiology 76;939-942, 1992 PHARMACODYNAMICS OF ROCURONIUM BROMIDE IN GERIATRICS ROCURONIUM BROMIDE IN THE ELDERLY (>65YR.)

Dose Time to Time to Maximum Clinical mg/kg >80% Block Block (min.) Duration (min.) (min.) .6 (n=31) 2.3 (1.0-8.3) 3.7 (1.3-11.3) 46 (22-73)

.9 (n+5) 2.0 (1.0-3.0) 2.5 (1.2-5.0) 62 49-75)

1.2 (n=7) 1.0 (0.8-3.5) 1.3 (1.2-4.7) 94 (64-138)

Rocuronium bromide package insert 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 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 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 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 CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE IN RENAL FAILURE Rocuronium bromide (0.6 mg/kg) Effects of Renal Failure on Onset of Neuromuscular Blockage Under Steady State 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 CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE IN HEPATIC DISEASE 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 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 THE PHARMACODYNAMICS OF ROCURONIUM BROMIDE IN THE OBESE Obesity defined as  30% of Ideal Body Weight

• Dose can be based on patient’s actual body weight

Rocuronium bromide package insert ROCURONIUM BROMIDE IN CONTINUOUS INFUSION 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 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 ROCURONIUM BROMIDE DRUG INTERACTIONS ROCURONIUM BROMIDE: DRUG INTERACTIONS

Intravenous : The use of propofol for Induction and maintenance of anesthesia does not alter clinical duration of recovery

Rocuronium bromide package insert ROCURONIUM BROMIDE: DRUG INTERACTIONS

Volatile Anesthetics: Rocuronium bromide requirements are reduced by approximately 10-25% when used with or isoflurane, but little change when used with halothane

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

Rocuronium bromide package insert ROCURONIUM BROMIDE CONCLUSIONS • Mono-quaternary steroidal drug • Structural relative of Vecuronium bromide • Rapid to intermediate . 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 : minimally by the kidneys Current Concepts in Neuromuscular Blockade

7776 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 study2 • Postoperative complications are very expensive Avoiding these is where the real cost savings accrue

1Ballantyne JC, et al. Anesth Analg. 1997; 85:476 2Berg H, et al. Acta Anaesthesiol Scand. 1997;41:1095 Rationale for Selection of NMBs: • 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