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Transcript of CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE Jerrold H. Levy, MD Professor of Anesthesiology Emory...
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CLINICAL PHARMACOLOGY OF
ROCURONIUM BROMIDE
Jerrold H. Levy, MDProfessor of Anesthesiology
Emory University School of Medicine Division of Cardiothoracic Anesthesiology
and Critical CareEmory HealthcareAtlanta, Georgia
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HISTORICAL PERSPECTIVES OF NEUROMUSCULAR BLOCKING
AGENTS
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INTRODUCTION OF NEW DRUGS1494 - 1942 Curare1947 - 1951 Succinylcholine chloride, Gallamine,
Metocurine, Decamethonium1960’s Alcuronium1970’s Pancuronium bromide, Fazadinium1980’s Vecuronium bromide, Atracurium besylate1990 Pipecuronium bromide1991 Doxacurium chloride1992 Mivacurium chloride1994 Rocuronium bromide1999 Rapacuronium bromide
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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
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THE IDEAL RELAXANT
• Nondepolarizing
• Rapid onset
• Dose-dependent duration
• No side-effects
• Elimination independent of organ function
• No active or toxic metabolites
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ONSET OF PARALYSIS IS AFFECTED BY:
• Dose (relative to ED95)
• Potency (number of molecules)
• Keo (chemistry/blood flow)
• Clearance
• Age
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PHARMACODYNAMICS OF ROCURONIUM BROMIDE
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ONSET OF ROCURONIUM BROMIDE
Onset: rapid to intermediate
(dose dependent)
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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
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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)
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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)
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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
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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)
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ROCURONIUM BROMIDERAPID SEQUENCE
INTUBATION
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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
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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%)
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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
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LOW DOSE PHARMACODYNAMICS: DURATIONRocuronium 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 minT 10-25 12 4 ± 1T 25-75 14 9 ± 1
Adapted from: Tullock et al Anesthesiology, vol 75, no. 3A, 1991
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CARDIOVASCULAR PROFILE OF ROCURONIUM BROMIDE
AND OTHER NEUROMUSCULAR BLOCKING AGENTS
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HISTAMINE RELEASING POTENTIAL
Significant Insignificant
Tubocurarine + + + Rocuronium bromide ±
Metocurine ++ Vecuronium bromide ±
Atracurium besylate + Pancuronium bromide ±
Mivacurium chloride + Pipecuronium bromide ±
Succinylcholine chloride + Doxacurium chloride ±
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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
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Muscle Relaxants
Vecuronium• No effects on HR, BP
• Requires reconstitution
• Reliable and controllable duration of action
• Slower onset
• Stable hemodynamics/no histamine release
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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
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Effects of Rocuronium on Heart Rate
Time (minutes)Time (minutes)
100100
9090
8080
7070
6060
5050
40400.00.0 1.01.0 2.02.0 3.03.0 4.04.0 5.05.0 6.06.0
Heart
Rate
(b
eats
/min
)H
eart
Rate
(b
eats
/min
)
Levy et al. Levy et al. Anesth AnalgAnesth Analg 1994;78,318-321. 1994;78,318-321.
600 mcg/kg600 mcg/kg900 mcg/kg900 mcg/kg1200 mcg/kg1200 mcg/kg
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Effects of Rocuronium on Mean Arterial Pressure
Time (minutes)Time (minutes)
100100
9090
8080
7070
6060
50500.00.0 1.01.0 2.02.0 3.03.0 4.04.0 5.05.0 6.06.0M
ean
Art
eri
al Pre
ssu
re (
mm
Hg
)M
ean
Art
eri
al Pre
ssu
re (
mm
Hg
)
600 mcg/kg600 mcg/kg900 mcg/kg900 mcg/kg1200 mcg/kg1200 mcg/kg
Levy et al. Levy et al. Anesth AnalgAnesth Analg 1994;78,318-321. 1994;78,318-321.
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Effects of Rocuronium on Histamine Release
Time (minutes)Time (minutes)0.00.0 1.01.0 2.02.0 3.03.0 4.04.0 5.05.0
Pla
sma H
ista
min
e (
ng
/ml)
Pla
sma H
ista
min
e (
ng
/ml)
Levy et al. Levy et al. Anesth AnalgAnesth Analg 1994;78,318-321. 1994;78,318-321.
600 mcg/kg600 mcg/kg900 mcg/kg900 mcg/kg1200 mcg/kg1200 mcg/kg
3.03.0
2.52.5
2.02.0
1.51.5
1.01.0
0.50.5
0.00.0
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ROCURONIUM BROMIDE:CARDIOVASCULAR PROFILE
• Favorable cardiovascular profile
• Histamine release unlikely
• Mild vagolytic activity
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PHARMACODYNAMICS OF ROCURONIUM
BROMIDE IN PEDIATRICS
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ONSET AND DURATIONOF ACTION OF ROCURONIUM BROMIDE IN INFANTS
(3 MOS.-1 YR. DURING N2O/HALOTHANE ANESTHESIADosemg/kg
Time to90% Block
(sec)
Onset(sec)
ClinicalDuration
(min)
Rocuronium bromide 0.6 37 ± 2 64 ± 10 41.9 ± 3.2(20-60) (20-180) (24.3-67.7)
Χ ± semAdapted from: Woellel et al Anesthesiology 76;939, 1992
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ONSET AND DURATION OF ACTION OF ROCURONIUM BROMIDE IN CHILDREN (1-5 YRS.)
DURING N2O/HALOTHANE ANESTHESIA
mg/kg Onset (Timeto Max
Block) (sec)
ClinicalDuration (min)
T25-75 (min)
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
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PHARMACODYNAMICS OF ROCURONIUM
BROMIDE IN GERIATRICS
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ROCURONIUM BROMIDE IN THE ELDERLY (>65YR.)
Dosemg/kg
Time to>80% Block
(min.)
Time to MaximumBlock (min.)
ClinicalDuration (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
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ROCURONIUM BROMIDE: INFLUENCE OF AGE
SummaryPediatrics (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
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ROCURONIUM BROMIDE: INFLUENCE OF AGE
SummaryPediatrics (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
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ROCURONIUM BROMIDE: INFLUENCE OF AGE
SummaryAdults (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
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ROCURONIUM BROMIDE: INFLUENCE OF AGE
SummaryGeriatric ( 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
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CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE
IN RENAL FAILURE
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Rocuronium bromide (0.6 mg/kg)Effects of Renal Failure on Onset
of 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
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CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE
IN HEPATIC DISEASE
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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
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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
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THE PHARMACODYNAMICS OF ROCURONIUM BROMIDE IN THE
OBESE
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Obesity defined as 30% of Ideal Body Weight
• Dose can be based on patient’s actual body weight
Rocuronium bromide package insert
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ROCURONIUM BROMIDE IN CONTINUOUS INFUSION
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ROCURONIUM BROMIDEContinuous Infusion
Recommended Initial Infusion Rate (Adult):• 0.01-0.012 mg/kg/min. initiated only after
spontaneous recovery from an intubating doseUpon reaching the desired level of neuromuscular block, the infusion of Rocuronium bromide must be individualized for each patient
Rocuronium bromide package insert
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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
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ROCURONIUM BROMIDE
DRUG INTERACTIONS
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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
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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
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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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ROCURONIUM BROMIDE: DRUG INTERACTIONS
Anticonvulsants:
shorter durations of neuromuscular block may occur and infusion rates may be higher
Rocuronium bromide package insert
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ROCURONIUM BROMIDECONCLUSIONS
• 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
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Current Conceptsin
Neuromuscular Blockade
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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 expensiveAvoiding these is where the real cost savings accrue
1Ballantyne JC, et al. Anesth Analg. 1997; 85:4762Berg H, et al. Acta Anaesthesiol Scand. 1997;41:1095
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• 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:Rationale for Selection of NMBs: