CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE · CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE ... Atracurium besylate ... DRUG INTERACTIONS Intravenous Anesthetics:

CLINICAL PHARMACOLOGY OF

ROCURONIUM BROMIDEJerrold H. Levy, MD

Professor of AnesthesiologyEmory University School of Medicine

Division of Cardiothoracic Anesthesiology and Critical CareEmory HealthcareAtlanta, Georgia

CLINICAL PHARMACOLOGY OF

ROCURONIUM BROMIDEJerrold H. Levy, MD

Professor of AnesthesiologyEmory University School of Medicine

Division of Cardiothoracic Anesthesiology and Critical CareEmory HealthcareAtlanta, Georgia

HISTORICAL PERSPECTIVES OF NEUROMUSCULAR BLOCKING

AGENTS

HISTORICAL PERSPECTIVES OF NEUROMUSCULAR BLOCKING

AGENTS

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

INTRODUCTION OF NEW DRUGS

Succinylcholine chloride, Gallamine, Metocurine, Decamethonium

Pancuronium bromide, FazadiniumVecuronium bromide, Atracurium besylatePipecuronium bromideDoxacurium chlorideMivacurium chlorideRocuronium bromideRapacuronium 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

STRUCTURAL CLASSES OF NONDEPOL.ARIZING RELAXANTS

Steroids: Rocuronium bromide, Vecuronium bromide, Pancuronium bromide, Pipecuronium bromide

Naturally occurring benzylisoquinolones: curare,

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

THE IDEAL RELAXANT

dependent duration

Elimination independent of organ functionNo active or toxic metabolites

ONSET OF PARALYSIS IS AFFECTED BY:

• Dose (relative to ED• Potency (number of molecules)• Keo (chemistry/blood flow)• Clearance• Age

ONSET OF PARALYSIS IS AFFECTED BY:

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

(chemistry/blood flow)

PHARMACODYNAMICS OF ROCURONIUM BROMIDE

PHARMACODYNAMICS OF ROCURONIUM BROMIDE

ONSET OF ROCURONIUM BROMIDE

Onset: rapid to intermediate(dose dependent)

ONSET OF ROCURONIUM BROMIDE

Onset: rapid to intermediate(dose dependent)

TRACHEAL INTUBATION

Pre-Medication MeperidineAtropine

Induction Propofol toAlfentanil to

Rocuronium bromide 0.6 mg/kg Succinylcholine chloride 1 mg/kgIntubation 60 sec. later

TRACHEAL INTUBATION

Meperidine 1 mg/kgAtropine 0.01 mg/kgPropofol to 2.5 mg/kgAlfentanil to 0.25 mg/kg

Rocuronium bromide 0.6 mg/kg ORSuccinylcholine chloride 1 mg/kg

60 sec. later

ROCURONIUM BROMIDE:TRACHEAL INTUBATION

• Median time to 80% block with 0.6 mg/kg is 60 seconds (0.4

• Median onset time with 0.6 mg/kg is 1.8 minutes (0.6-13 minutes)


80% block with 0.6 mg/kg is 60 seconds (0.4-6.0 minutes)Median onset time with 0.6 mg/kg is

13 minutes)


• Median time to 80% blockade with 0.45 mg/kg is 78 seconds (0.8minutes)

• Median onset time with 0.45 mg/kg is 3.0 minutes (1.3-8.2 minutes)


80% blockade with 0.45 mg/kg is 78 seconds (0.8-6.2

Median onset time with 0.45 mg/kg is 8.2 minutes)

LOW DOSE PHARMACODYNAMICS:CLINICAL PARAMETERS

Mean maximum blockade

Mean time to 80% blockade

Mean time to maximum blockade

Mean time to completion of intubation

LOW DOSE PHARMACODYNAMICS:CLINICAL PARAMETERS

Rocuronium bromideDose: .45 mg/kg (n = 14)

96 ± 5%

117 ± 24 seconds

214 ± 25 seconds

159 ± 25 seconds



• Median onset time with 0.9 mg/kg is 84 seconds (0.8


• Median onset time with 1.2 mg/kg is 60 seconds (0.6



Median onset time with 0.9 mg/kg is 84 seconds (0.8-6.2 minutes)


Median onset time with 1.2 mg/kg is 60 seconds (0.6-4.7 minutes)

ROCURONIUM BROMIDERAPID SEQUENCE

INTUBATION

ROCURONIUM BROMIDERAPID SEQUENCE

INTUBATION

ROCURONIUM BROMIDE RAPID SEQUENCE INTUBATION

n = 230 (six clinical trials)

Premedication:midazolam or temazepamInduction: thiopental (3-6 mg/kg)

or +propofol (1.5 - 2.5 mg/kg)

Rocuronium bromide dose: 0.6 mg/kg

Succinylcholine chloride dose: 1-1.5 mg/kg

ROCURONIUM BROMIDE RAPID SEQUENCE INTUBATION

fentanyl (2-5 mcg/kg) or

alfentanil (1 mg)

0.6 mg/kg

1.5 mg/kg

RAPID SEQUENCE INTUBATIONRapid sequence intubation: excellent-to-good conditions achieved within 60 administration in most patients

Dose

Rocuronium bromide (n=120) 0.6 mg/kg

Succinylcholine chloride (n=110) 1.0-1.5 mg/kg

RAPID SEQUENCE INTUBATIONgood conditions achieved within 60 - 90 seconds of

Percentage of patients with excellent-to-good conditions

99% (95% confidence interval 95%-99.9%)

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

DURATION OF ACTION OF NEUROMUSCULAR BLOCKING AGENTS

Succinylcholine chlorideMivacurium chloride

Intermediate: Rocuronium bromide, Vecuronium bromide, Atracurium besylatePancuronium bromide, curare, metocurine, Pipecuronium bromide, Doxacurium chloride

LOW DOSE PHARMACODYNAMICS: DURATION

From injection to Recovery of T1 n10% of control 1225% of control 1490% of control 14

SpontaneousRecovery nT 10-25 12T 25-75 14

Adapted from: Tullock et al Anesthesiology, vol 75, no. 3A, 1991

LOW DOSE PHARMACODYNAMICS: DURATIONRocuronium bromideDose: .45 mg/kg

min18 ± 121 ± 136 ± 2

min4 ± 19 ± 1

CARDIOVASCULAR PROFILE OF ROCURONIUM BROMIDE

AND OTHER NEUROMUSCULAR BLOCKING AGENTS

CARDIOVASCULAR PROFILE OF ROCURONIUM BROMIDE

AND OTHER NEUROMUSCULAR BLOCKING AGENTS

HISTAMINE RELEASING POTENTIAL

Significant

Tubocurarine + + +Metocurine ++Atracurium besylate +Mivacurium chloride +Succinylcholine chloride +

HISTAMINE RELEASING POTENTIAL

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

Vagolytic: increases heart rate, may require beta blockade

Intermediate duration of action

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

No effects on HR, BP

Requires reconstitution

Reliable and controllable duration of action

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

Muscle Relaxants

Minimal effects on HR, BP

Controllable duration of action

Stable hemodynamics/minimal histamine release

Potential for bronchospasm led to its removal in

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

H

eart R

ate (beats/m

in)

H

eart R

ate (beats/m

in)

Levy et al. Levy et al. Anesth AnalgAnesth Analg 1994;78,3181994;78,318--321.321.

Effects of Rocuronium on Heart Rate

Time (minutes)Time (minutes)2.02.0 3.03.0 4.04.0 5.05.0 6.06.0

600 mcg/kg600 mcg/kg900 mcg/kg900 mcg/kg1200 mcg/kg1200 mcg/kg

Effects of Rocuronium on Mean Arterial Pressure

Time (minutes)Time (minutes)

100100

9090

8080

7070

6060

50500.00.0 1.01.0 2.02.0M

ean Arterial Pressure (m

m

H

g)

M

ean Arterial Pressure (m

m

H

g)


Effects of Rocuronium on Mean Arterial Pressure

Time (minutes)Time (minutes)2.02.0 3.03.0 4.04.0 5.05.0 6.06.0


Effects of Rocuronium on Histamine Release

Time (minutes)Time (minutes)0.00.0 1.01.0

Plasm

a H

istam

ine (ng/m

l)

Plasm

a H

istam

ine (ng/m

l)


3.03.0

2.52.5

2.02.0

1.51.5

1.01.0

0.50.5

0.00.0

Effects of Rocuronium on Histamine Release

Time (minutes)Time (minutes)2.02.0 3.03.0 4.04.0 5.05.0


ROCURONIUM BROMIDE:CARDIOVASCULAR PROFILE

• Favorable cardiovascular profile• Histamine release unlikely• Mild vagolytic activity

ROCURONIUM BROMIDE:CARDIOVASCULAR PROFILE

Favorable cardiovascular profileHistamine release unlikelyMild vagolytic activity

PHARMACODYNAMICS OF ROCURONIUM

BROMIDE IN PEDIATRICS


BROMIDE IN PEDIATRICS

ONSET AND DURATIONOF ACTION OF ROCURONIUM BROMIDE IN INFANTS

(3 MOS.-1 YR. DURING NANESTHESIADosemg/kg 90% Block

Rocuronium bromide 0.6

Χ ± semAdapted from: Woellel et al Anesthesiology 76;939, 1992

ONSET AND DURATIONOF ACTION OF ROCURONIUM BROMIDE IN INFANTS

1 YR. DURING N2O/HALOTHANE ANESTHESIA

Time to90% Block

(sec)

Onset(sec)

ClinicalDuration

(min)

37 ± 2 64 ± 10 41.9 ± 3.2(20-60) (20-180) (24.3-67.7)

al Anesthesiology 76;939, 1992

ONSET AND DURATION OF ACTION OF ROCURONIUM BROMIDE IN CHILDREN (1

DURING N2O/HALOTHANE ANESTHESIA

mg/kg Onset (Timeto Max

Block) (sec)

Rocuronium bromide 0.6 78

(Range) (42-168)

Adapted from: Woettel, Brandom, et al Anesthesiology 76;939-942, 1992

ONSET AND DURATION OF ACTION OF ROCURONIUM BROMIDE IN CHILDREN (1-5 YRS.)

O/HALOTHANE ANESTHESIA

Onset (Timeto Max

Block) (sec)

ClinicalDuration (min)

T25-75 (min)

78 26.7 11.0

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

Brandom, et al Anesthesiology 76;939-942, 1992


BROMIDE IN GERIATRICS


BROMIDE IN GERIATRICS

ROCURONIUM BROMIDE IN THE ELDERLY (

Dosemg/kg

Time to>80% Block

(min.)

Time to Maximum

.6 (n=31) 2.3 (1.0-8.3)

.9 (n+5) 2.0 (1.0-3.0)

1.2 (n=7) 1.0 (0.8-3.5)

Rocuronium bromide package insert

ROCURONIUM BROMIDE IN THE ELDERLY (>65YR.)

Time to MaximumBlock (min.)

ClinicalDuration (min.)

3.7 (1.3-11.3) 46 (22-73)

2.5 (1.2-5.0) 62 49-75)

1.3 (1.2-4.7) 94 (64-138)

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)



0.6 mg/kg Rocuronium bromide produces excellent to good intubating conditions within 1 minute, with 41 minutes of clinical relaxation


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)



0.6 mg/kg Rocuronium bromide produces excellent to good intubating conditions within 1 minute, with 27 minutes of clinical relaxation


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)



0.6 mg/kg Rocuronium bromide produces excellent to good intubating conditions within 60 seconds, with 31 minutes of clinical relaxation


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)



0.6 mg/kg Rocuronium bromide produces excellent to good intubating conditions within 2.3 minutes, with 46 minutes of clinical relaxation

CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE

IN RENAL FAILURE


IN RENAL FAILURE

Rocuronium bromide (0.6 mg/kg)Effects of Renal Failure on Onset

of Neuromuscular BlockageUnder Steady State Isoflurane Anesthesia

Normal Renal Function*(n = 10)

Onset Time (sec) 69 ± 24

*Values are mean ± SD† Patients with end-stage renal disease undergoing cadaver renal transplantation

Adapted from: Szenochradsky et al Anesthesiology 77;899

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)63 ± 17

stage renal disease undergoing cadaver renal transplantation

Adapted from: Szenochradsky et al Anesthesiology 77;899-904, 1992


IN HEPATIC DISEASE


IN HEPATIC DISEASE

ROCURONIUM BROMIDEEffects of Hepatic Disease Under Steady State

Isoflurane Anesthesia

Neuromuscular Effects• Onset unchanged• Recovery increased• Larger or repeat doses may have prolonged effect




Larger or repeat doses may have prolonged effect



Pharmacokinetics• Clearance unchanged• Central and steady state distribution volumes and

elimination half-life increased




Central and steady state distribution volumes and life increased

THE PHARMACODYNAMICS OF ROCURONIUM BROMIDE IN THE

OBESE

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


30% of Ideal Body Weight

Dose can be based on patient’s actual body weight

ROCURONIUM BROMIDE IN CONTINUOUS INFUSION

ROCURONIUM BROMIDE IN CONTINUOUS INFUSION

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



Recommended Initial Infusion Rate (Adult):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


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



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 DRUG INTERACTIONS

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



The use of propofol for Induction and maintenance of anesthesia does not alter clinical


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 requirements are reduced by 25% when used with enflurane

or isoflurane, but little change when used with


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)



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


Anticonvulsants:shorter durations of neuromuscular block may occur and infusion rates may be higher



shorter durations of neuromuscular block may occur and infusion rates may be higher

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

ROCURONIUM BROMIDECONCLUSIONS

quaternary steroidal drugStructural relative of Vecuronium bromideRapid to intermediate onset of action. Significantly more rapid than Vecuronium bromide or Atracurium besylateFor use in outpatient or inpatient procedures of varying

suitable for rapid sequence intubationFavorable cardiovascular profilesEliminated mainly by liver: minimally by the kidneys

Current Conceptsin

Neuromuscular Blockade

7776

Current Conceptsin

Neuromuscular Blockade

Neuromuscular Agents: Costs of Care• Cost of care acquisition cost

• The real, substantial savings accrue from use of intermediateshort-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 Avoiding 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

Neuromuscular Agents: Costs of Care

The real, substantial savings accrue from use of intermediate- and

acting drugs are associated with prolonged

Fast recovery means shorter risk periods of residual blockade. This translates into fewer postoperative complications, as shown in the

Postoperative complications are very expensiveAvoiding these is where the real cost savings accrue

Ballantyne JC, et al. Anesth Analg. 1997; 85:476Berg H, et al. Acta Anaesthesiol Scand. 1997;41:1095

• 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:

Nondepolarizing vs depolarizing independent elimination

Clinically significant active or toxic metabolites

Rationale for Selection of NMBs:Rationale for Selection of NMBs:

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CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE · CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE ... Atracurium besylate ... DRUG INTERACTIONS Intravenous Anesthetics: