CLINICAL PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Division of.

CLINICAL PHARMACOLOGY OF NEUROMUSCULAR

BLOCKING AGENTS

Jerrold H. Levy, MDProfessor of Anesthesiology

Emory University School of Medicine Division of Cardiothoracic Anesthesiology

and Critical CareEmory HealthcareAtlanta, Georgia

HISTORY OF NEUROMUSCULAR BLOCKING AGENTS AND CLINICAL

DEVELOPMENT

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 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 benzylisoquinolines: 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

Neuromuscular Blocking Agents Neuromuscular Blocking Agents and Patient Evaluationand Patient Evaluation

Assessing Postoperative Assessing Postoperative Neuromuscular FunctionNeuromuscular FunctionAssessing Postoperative Assessing Postoperative Neuromuscular FunctionNeuromuscular Function

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

Assessing Postoperative Neuromuscular Function

CLINICAL ASSESSMENTCLINICAL ASSESSMENT

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

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

Assessing Postoperative Neuromuscular Function

Train-of-Four (TOF) Fade RatioTrain-of-Four (TOF) Fade Ratio

9999999997979797100100100100100%100%100%100%

959595959191919110010010010090%90%90%90%

949494948888888810010010010080%80%80%80%

92929292828282829797979770%*70%*70%*70%*

95959595707070709191919160%60%60%60%

100100100100100100100100100100100100Control Control =100=100

Control Control =100=100

Peak Exp. Flow Rate

Inspiratory ForceVital CapacityTOF Ratio

Assessing Postoperative Neuromuscular Function

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

THE ORIGIN OF THE GOLD STANDARDTHE ORIGIN OF THE GOLD STANDARD

* Historically regarded as the Gold Standard * Historically regarded as the Gold Standard * Historically regarded as the Gold Standard * Historically regarded as the Gold Standard

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

Assessing Postoperative Neuromuscular 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 Function

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

ASSESSING TOF FADE RATIOASSESSING TOF FADE RATIOASSESSING TOF FADE RATIOASSESSING TOF FADE RATIO

1Viby-Mogensen J, et al. Anesthesiology. 1979;50:5392Kopman AF, et al. Anesthesiology. 1994;81:1394

1Viby-Mogensen J, et al. Anesthesiology. 1979;50:5392Kopman AF, et al. Anesthesiology. 1994;81:1394

Assessing Postoperative Neuromuscular Function

Recovery is inadequate if fade is detected1,2

Clinical trials are needed to demonstrate measurement techniques for TOF ratios of 0.902

11Eriksson, LI, et al. Eriksson, LI, et al. Anesthesiology.Anesthesiology. 1997;87:1035 1997;87:103522Bevan, DR, et al. Bevan, DR, et al. AnesthesiologyAnesthesiology. 1988;69:272. 1988;69:272

11Eriksson, LI, et al. Eriksson, LI, et al. Anesthesiology.Anesthesiology. 1997;87:1035 1997;87:103522Bevan, DR, et al. Bevan, DR, et al. AnesthesiologyAnesthesiology. 1988;69:272. 1988;69:272

TOF FADE RATIO: CONCLUSIONTOF FADE RATIO: CONCLUSIONTOF FADE RATIO: CONCLUSIONTOF FADE RATIO: CONCLUSION

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

Neuromuscular Blockers:Chemical Structure & Key Characteristics

AminosteroidsAminosteroids

Savage DS, et al. Br J Anaesth. 1980;52 Suppl 1:3SDurant NN, et al. J Pharm Pharmacol. 1979:31(12):831Marshall IG, et al. Br J Anaesth. 1980;52 Suppl 1:11S

Savage DS, et al. Br J Anaesth. 1980;52 Suppl 1:3SDurant NN, et al. J Pharm Pharmacol. 1979:31(12):831Marshall IG, et al. Br J Anaesth. 1980;52 Suppl 1:11S

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

Neuromuscular Blockers:Chemical Structure & Key Characteristics

BenzylisoquinolinesBenzylisoquinolines

1Stenlake JB, et al. Br J Anaesth. 1983;55;3S2Ali HH, et al. Br J Anaesth. 1983;55:107S

1Stenlake JB, et al. Br J Anaesth. 1983;55;3S2Ali HH, et al. Br J Anaesth. 1983;55:107S

Ultra- Ultra- ShortShort ShortShort

Clinical durationClinical duration(injection to T(injection to T2525))Clinical durationClinical duration(injection to T(injection to T2525))

6 - 86 - 86 - 86 - 8 12 - 2012 - 2012 - 2012 - 20 30 - 4530 - 4530 - 4530 - 45 >60>60>60>60

<15<15<15<15 25 - 3025 - 3025 - 3025 - 30 50 - 7050 - 7050 - 7050 - 70 90 -18090 -18090 -18090 -180

Classification of Neuromuscular Classification of Neuromuscular Blockers by Duration of Action (Minutes)Blockers by Duration of Action (Minutes)

LongLongIntermediateIntermediate

Recovery time Recovery time (injection to T(injection to T9595))

Recovery time Recovery time (injection to T(injection to T9595))

Recovery index (TRecovery index (T25 25

to Tto T7575))Recovery index (TRecovery index (T25 25

to Tto T7575))

ExamplesExamplesExamplesExamples

2 - 32 - 32 - 32 - 3 6666 10 -1510 -1510 -1510 -15 >30>30>30>30

succinyl-succinyl-cholinecholine

succinyl-succinyl-cholinecholine mivacuriummivacuriummivacuriummivacurium cisatracuriumcisatracuriumcisatracuriumcisatracurium doxacuriumdoxacuriumdoxacuriumdoxacurium

Assumes bolus dose = 2x EDAssumes bolus dose = 2x ED9595Assumes bolus dose = 2x EDAssumes bolus dose = 2x ED959511AnectineAnectine®® (succinylcholine chloride) Package Insert (succinylcholine chloride) Package Insert22MivacronMivacron®® (mivacurium chloride) Package Insert (mivacurium chloride) Package Insert33NimbexNimbex®® (cisatracurium besylate) Package Insert (cisatracurium besylate) Package Insert44NuromaxNuromax®® (doxacurium chloride) Package Insert (doxacurium chloride) Package Insert

11AnectineAnectine®® (succinylcholine chloride) Package Insert (succinylcholine chloride) Package Insert22MivacronMivacron®® (mivacurium chloride) Package Insert (mivacurium chloride) Package Insert33NimbexNimbex®® (cisatracurium besylate) Package Insert (cisatracurium besylate) Package Insert44NuromaxNuromax®® (doxacurium chloride) Package Insert (doxacurium chloride) Package Insert

1122 33 44

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

AGENTSHemodynamics, histamine release, and

other aspects

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

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

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

)

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

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

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)

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

3.03.0

2.52.5

2.02.0

1.51.5

1.01.0

0.50.5

0.00.0

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

COSTS OF NEUROMUSCULAR BLOCKING AGENTS AND

SELECTION CRITERIA

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

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

Neuromuscular Agents:Costs of Care

Neuromuscular Agents:Costs of Care

1Ballantyne JC, et al. Anesth Analg. 1997; 85:4762Berg H, et al. Acta Anaesthesiol Scand. 1997;41:1095

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 NMBAs:Rationale for Selection of NMBAs: