CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE

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

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

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)


• 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



• 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 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

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: 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

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 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

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

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

)



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)



3.03.0

2.52.5

2.02.0

1.51.5

1.01.0

0.50.5

0.00.0

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 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

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

PHARMACODYNAMICS OF ROCURONIUM

BROMIDE IN GERIATRICS

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

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)



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)



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)



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)


CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE

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* 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 BROMIDEEffects of Hepatic Disease Under Steady State

Isoflurane Anesthesia

Neuromuscular Effects

• Onset unchanged

• Recovery increased

• Larger or repeat doses may have prolonged effect


ROCURONIUM BROMIDEEffects of Hepatic Disease Under Steady State

Isoflurane Anesthesia

Pharmacokinetics

• Clearance unchanged

• Central and steady state distribution volumes and elimination half-life increased


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 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


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

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



Volatile Anesthetics:

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



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)



Anticonvulsants:

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

Current Conceptsin

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 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

• 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:

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CLINICAL PHARMACOLOGY OF ROCURONIUM BROMIDE