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CLINICAL PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS 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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clinical pharmacology of neuromuscular blocking agents

CLINICAL PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS

Jerrold H. Levy, MD

Professor of Anesthesiology

Emory University School of Medicine

Division of Cardiothoracic Anesthesiology and Critical Care

Emory Healthcare

Atlanta, Georgia

history
HISTORY

1494 - Tales of travelers killed by poison darts

1551 - Ourari” or “cururu” meaning “bird killer”

1812 - Curarized cat kept alive by artificial respiration

1912 - Curare used to prevent fractures during ECT

1941 - Initial use by Griffith, Culler, and Rovenstine

1951 - Succinylcholine chloride first used in Stockholm

introduction of new drugs
INTRODUCTION OF NEW DRUGS

1494 - 1942 Curare

1947 - 1951 Succinylcholine chloride, Gallamine, Metocurine, Decamethonium

1960’s Alcuronium

1970’s Pancuronium bromide, Fazadinium

1980’s Vecuronium bromide, Atracurium besylate

1990 Pipecuronium bromide

1991 Doxacurium chloride

1992 Mivacurium chloride

1994 Rocuronium bromide

1999 Rapacuronium bromide

structural classes of nondepol arizing relaxants
STRUCTURAL CLASSES OF NONDEPOL.ARIZING RELAXANTS
  • Steroids: Rocuronium bromide, Vecuronium bromide, Pancuronium bromide, Pipecuronium bromide
  • Naturally occurring benzylisoquinolines: curare, metocurine
  • Benzylisoquinoliniums: Atracurium besylate, Mivacurium chloride, Doxacurium chloride
the ideal relaxant
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
ONSET OF PARALYSIS IS AFFECTED BY:
  • Dose (relative to ED95)
  • Potency (number of molecules)
  • Keo (chemistry/blood flow)
  • Clearance
  • Age
neuromuscular blocking agents and patient evaluation

Neuromuscular Blocking Agents and Patient Evaluation

Assessing Postoperative Neuromuscular Function

assessing postoperative neuromuscular function
Assessing Postoperative Neuromuscular Function

CLINICAL ASSESSMENT

  • Sustained 5-second head lift
  • Ability to appose incisors (clench teeth)
  • Negative inspiratory force > – 40 cm H2O
  • Ability to open eyes wide for 5 seconds
  • Hand-grip strength
  • Sustained arm/leg lift
  • Quality of speaking voice
  • Tongue protrusion

Kopman AF, et al. Anesthesiology, 1997:86;765

assessing postoperative neuromuscular function10
Assessing Postoperative Neuromuscular Function

Train-of-Four (TOF) Fade Ratio

Ali HH, et al. Br J Anaesth. 1975;47:570

assessing postoperative neuromuscular function11
Assessing Postoperative Neuromuscular Function

THE ORIGIN OF THE GOLD STANDARD

TOF Ratio

Vital Capacity

Inspiratory Force

Peak Exp. Flow Rate

Control =100

100

100

100

60%

91

70

95

70%*

97

82

92

100

88

94

80%

100

91

95

90%

100

97

99

100%

* Historically regarded as the Gold Standard

Ali HH, et al. Br J Anaesth. 1975;47:570

assessing postoperative neuromuscular function12
Assessing Postoperative Neuromuscular Function

NEW DATA SUGGEST THAT A TOF OF 0.90 MAY BE NEEDED TO ENSURE NORMAL FUNCTION

  • Kopman: A TOF > 0.90 compatible with normal clinical tests (Anesthesiology. 1997;86:765)
  • Eriksson: Pharyngeal function normal at TOF 0.90 (Anesthesiology. 1997;87:1035)
assessing postoperative neuromuscular function13
Assessing Postoperative Neuromuscular Function

ASSESSING TOF FADE RATIO

  • Patients are often returned to the PACU with residual paralysis1
  • The TOF ratio of 0.70 may be inadequate for discharge of an ambulatory patient1
  • TOF ratios  0.40 are difficult to assess clinically2

1Viby-Mogensen J, et al. Anesthesiology. 1979;50:539

2Kopman AF, et al. Anesthesiology. 1994;81:1394

assessing postoperative neuromuscular function14
Assessing Postoperative Neuromuscular Function

TOF FADE RATIO: CONCLUSION

  • Recovery is inadequate if fade is detected1,2
  • Clinical trials are needed to demonstrate measurement techniques for TOF ratios of 0.902

1Eriksson, LI, et al. Anesthesiology. 1997;87:1035

2Bevan, DR, et al. Anesthesiology. 1988;69:272

neuromuscular blockers chemical structure key characteristics
Neuromuscular Blockers:Chemical Structure & Key Characteristics

Aminosteroids

  • Vagolytic
    • Partially block cardiac muscarinic receptors involved in heart rate slowing, resulting in increased heart rate:
      • rapacuronium > pancuronium > rocuronium > vecuronium
  • Generally do not promote histamine release
    • Exception: rapacuronium
  • Organ-dependent elimination
    • Kidneys and liver

Savage DS, et al. Br J Anaesth. 1980;52 Suppl 1:3S

Durant NN, et al. J Pharm Pharmacol. 1979:31(12):831

Marshall IG, et al. Br J Anaesth. 1980;52 Suppl 1:11S

neuromuscular blockers chemical structure key characteristics16
Neuromuscular Blockers:Chemical Structure & Key Characteristics

Benzylisoquinolines

  • Absence of vagolytic effect
    • these drugs do not block cardiac-vagal (muscarinic) receptors
  • Histamine release
    • dTc > atracurium > mivacurium > cisatracurium
    • can cause rare bronchospasm, decreased blood pressure, increase of heart rate
  • Generally organ-independent elimination1
    • esp: atracurium, cisatracurium, mivacurium
  • Noncumulative2

1Stenlake JB, et al. Br J Anaesth. 1983;55;3S

2Ali HH, et al. Br J Anaesth. 1983;55:107S

classification of neuromuscular blockers by duration of action minutes
Classification of Neuromuscular Blockers by Duration of Action (Minutes)

Ultra- Short

Long

Short

Intermediate

Clinical duration

(injection to T25)

6 - 8

12 - 20

30 - 45

>60

Recovery time (injection to T95)

25 - 30

50 - 70

90 -180

<15

Recovery index (T25 to T75)

2 - 3

6

10 -15

>30

4

2

3

succinyl-choline

Examples

cisatracurium

doxacurium

mivacurium

1

Assumes bolus dose = 2x ED95

1Anectine® (succinylcholine chloride) Package Insert

2Mivacron® (mivacurium chloride) Package Insert

3Nimbex® (cisatracurium besylate) Package Insert

4Nuromax® (doxacurium chloride) Package Insert

duration of action of neuromuscular blocking agents
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
cardiovascular profile of neuromuscular blocking agents

CARDIOVASCULAR PROFILE OF NEUROMUSCULAR BLOCKING AGENTS

Hemodynamics, histamine release, and other aspects

histamine releasing potential
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
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 relaxants22
Muscle Relaxants

Vecuronium

  • No effects on HR, BP
  • Requires reconstitution
  • Reliable and controllable duration of action
  • Slower onset
  • Stable hemodynamics/no histamine release
muscle relaxants23
Muscle Relaxants

Rocuronium

  • No effects on HR, BP
  • Easy to use, liquid, no refrigeration
  • Reliable and controllable duration of action
  • Fast onset
  • Stable hemodynamics/no histamine release
effects of rocuronium on heart rate

100

600 mcg/kg

900 mcg/kg

1200 mcg/kg

90

80

Heart Rate (beats/min)

70

60

50

40

0.0

1.0

2.0

3.0

4.0

5.0

6.0

Time (minutes)

Effects of Rocuronium on Heart Rate

Levy et al. Anesth Analg 1994;78,318-321.

effects of rocuronium on mean arterial pressure

600 mcg/kg

900 mcg/kg

1200 mcg/kg

100

90

Effects of Rocuronium on Mean Arterial Pressure

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 1994;78,318-321.

effects of rocuronium on histamine release

600 mcg/kg

900 mcg/kg

1200 mcg/kg

3.0

2.5

Effects of Rocuronium on Histamine Release

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 1994;78,318-321.

muscle relaxants27
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
neuromuscular agents costs of care
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

slide30

Rationale for Selection of NMBAs:

  • 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