CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE

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

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HISTORICAL PERSPECTIVES OF NEUROMUSCULAR BLOCKING
AGENTS
3
INTRODUCTION OF NEW DRUGS

• 1494 - 1942 Curare
• 1947 - 1951 Succinylcholine chloride, Gallamine,
  Metocurine, Decamethonium
• 1960s Alcuronium
• 1970s Pancuronium bromide, Fazadinium
• 1980s Vecuronium bromide, Atracurium besylate
• 1990 Pipecuronium bromide
• 1991 Doxacurium chloride
• 1992 Mivacurium chloride
• 1994 Rocuronium bromide
• 1999 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 BROMIDETRACHEAL 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 BROMIDETRACHEAL 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 PHARMACODYNAMICSCLINICAL 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 BROMIDETRACHEAL 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 (n120) 0.6 mg/kg 99 (95
  confidence
• interval 95-99.9)
• Succinylcholine chloride (n110) 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 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

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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
Levy et al. Anesth Analg 199478,318-321.
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Effects of Rocuronium on Mean Arterial Pressure
100
90
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 199478,318-321.
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Effects of Rocuronium on Histamine Release
3.0
2.5
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 199478,318-321.
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ROCURONIUM BROMIDECARDIOVASCULAR 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 ANESTHESIA
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ONSET AND DURATION OF ACTION OF ROCURONIUM
BROMIDE IN CHILDREN (1-5 YRS.) DURING
N2O/HALOTHANE ANESTHESIA
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PHARMACODYNAMICS OF ROCURONIUM BROMIDE IN
GERIATRICS
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ROCURONIUM BROMIDE IN THE ELDERLY (gt65YR.)
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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

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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

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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

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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

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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 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
  77899-904, 1992

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CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDEIN
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
43

• Obesity defined as ? 30 of Ideal Body Weight
• Dose can be based on patients 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 dose
• 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 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 ConceptsinNeuromuscular Blockade
7776
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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 85476
• 2Berg H, et al. Acta Anaesthesiol Scand.
  1997411095

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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