Transcript 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
INTRODUCTION OF NEW DRUGS
1494 - 1942
1947 - 1951
1960’s
1970’s
1980’s
1990
1991
1992
1994
1999
Curare
Succinylcholine chloride, Gallamine,
Metocurine, Decamethonium
Alcuronium
Pancuronium bromide, Fazadinium
Vecuronium bromide, Atracurium besylate
Pipecuronium bromide
Doxacurium chloride
Mivacurium chloride
Rocuronium bromide
Rapacuronium bromide
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
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
PHARMACODYNAMICS OF
ROCURONIUM BROMIDE
ONSET OF ROCURONIUM
BROMIDE
Onset: rapid to intermediate
(dose dependent)
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
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:midazolam or temazepam
Induction:
thiopental (3-6 mg/kg)
or
+
propofol (1.5 - 2.5 mg/kg)
fentanyl (2-5 mcg/kg)
or
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
Rocuronium bromide (n=120)
Dose
Percentage of patients with
excellent-to-good conditions
0.6 mg/kg
99% (95% confidence
interval 95%-99.9%)
98% (95% confidence
interval 95%-99.8%)
Succinylcholine chloride (n=110) 1.0-1.5 mg/kg
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
10% of control
25% of control
90% of control
n
12
14
14
min
18 ± 1
21 ± 1
36 ± 2
Spontaneous
Recovery
T 10-25
T 25-75
n
12
14
min
4±1
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
Tubocurarine
Metocurine
Atracurium besylate
Mivacurium chloride
Succinylcholine chloride
Insignificant
+++
++
+
+
+
Rocuronium bromide
Vecuronium bromide
Pancuronium bromide
Pipecuronium bromide
Doxacurium chloride
±
±
±
±
±
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
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
600 mcg/kg
900 mcg/kg
1200 mcg/kg
Heart Rate (beats/min)
100
90
80
70
60
50
40
0.0
Levy et al. Anesth Analg 1994;78,318-321.
1.0
2.0 3.0 4.0 5.0
Time (minutes)
6.0
Mean Arterial Pressure (mmHg)
Effects of Rocuronium on Mean Arterial
Pressure
600 mcg/kg
100
900 mcg/kg
1200 mcg/kg
90
80
70
60
50
0.0
Levy et al. Anesth Analg 1994;78,318-321.
1.0
2.0 3.0 4.0 5.0
Time (minutes)
6.0
Plasma Histamine (ng/ml)
Effects of Rocuronium on Histamine Release
3.0
2.5
600 mcg/kg
900 mcg/kg
1200 mcg/kg
2.0
1.5
1.0
0.5
0.0
0.0
Levy et al. Anesth Analg 1994;78,318-321.
1.0
2.0
3.0 4.0
Time (minutes)
5.0
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/HALOTHANE
ANESTHESIA
Rocuronium bromide
Dose
mg/kg
Time to
90% Block
(sec)
0.6
37 ± 2
(20-60)
Χ ± sem
Adapted from: Woellel et al Anesthesiology 76;939, 1992
Onset
(sec)
Clinical
Duration
(min)
64 ± 10 41.9 ± 3.2
(20-180) (24.3-67.7)
ONSET AND DURATION OF ACTION OF
ROCURONIUM BROMIDE IN CHILDREN (1-5 YRS.)
DURING N2O/HALOTHANE ANESTHESIA
mg/kg
Rocuronium bromide
(Range)
0.6
Onset (Time
Clinical
to Max
Duration (min)
Block) (sec)
T25-75 (min)
78
26.7
11.0
(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
mg/kg
.6 (n=31)
Time to
>80% Block
(min.)
2.3 (1.0-8.3)
.9 (n+5)
1.2 (n=7)
Time to Maximum
Clinical
Block (min.)
Duration (min.)
3.7 (1.3-11.3)
46 (22-73)
2.0 (1.0-3.0)
2.5 (1.2-5.0)
62 49-75)
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 Isoflurane Anesthesia
Normal Renal Function*
(n = 10)
Onset Time (sec)
69 ± 24
Renal Transplantation*†
(n = 10)
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 Anesthetics:
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 enflurane
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 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
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:
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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