1. NEUROMUSCULAR
BLOCKING AGENTS
Carlos Darcy Alves Bersot TSA.SBA
MD RESPONSÁVEL PELO CET H.F.LAGOA
Médico Anestesiologista do Hospital Federal da Lagoa-SUS
Médico Anestesiologista do Hospital Pedro Ernesto-UERJ

2. Key Concepts
•Muscle relaxation does not ensure unconsciousness, amnesia, or analgesia
•Neuromuscular blocking agents are used to improve conditions for tracheal intubation, to provide
immobility during surgery, and to facilitate mechanical ventilation.
•Depolarizing muscle relaxants act as acetylcholine (ACh) receptor agonists, whereas
nondepolarizing muscle relaxants function as competitive antagonists.
•Depolarizing muscle relaxants are not metabolized by acetylcholinesterase, they diffuse away
from the neuromuscular junction and are hydrolyzed in the plasma and liver by another enzyme,
pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or
butyrylcholinesterase).
•With the exception of mivacurium, nondepolarizing agents are not significantly metabolized by
either acetylcholinesterase or pseudocholinesterase. Reversal of their blockade depends on
redistribution, gradual metabolism, and excretion of the relaxant by the body, or administration of
specific reversal agents (eg, cholinesterase inhibitors) that inhibit acetylcholinesterase enzyme
activity.
•Compared with patients with low enzyme levels or heterozygous atypical enzyme in whom
blockade duration is doubled or tripled, patients with homozygous atypical enzyme will have a
very long blockade (eg, 4–6 h) following succinylcholine administration.
•Succinylcholine is considered contraindicated in the routine management of children and
adolescents because of the risk of hyperkalemia, rhabdomyolysis, and cardiac arrest in children with
undiagnosed myopathies

3. •Normal muscle releases enough potassium during succinylcholine-induced depolarization to raise
serum potassium by 0.5 mEq/L. Although this is usually insignificant in patients with normal baseline
potassium levels, a life-threatening potassium elevation is possible in patients with burn injury,
massive trauma, neurological disorders, and several other conditions
•Doxacurium, pancuronium, vecuronium, and pipecuronium are partially excreted by the kidneys, and
their action is prolonged in patients with renal failure.
•Atracurium and cisatracurium undergo degradation in plasma at physiological pH and temperature
by organ-independent Hofmann elimination. The resulting metabolites (a monoquaternary acrylate
and laudanosine) have no intrinsic neuromuscular blocking effects
•Hypertension and tachycardia may occur in patients given pancuronium. These cardiovascular
effects are caused by the combination of vagal blockade and catecholamine release from adrenergic
nerve endings
•Long-term administration of vecuronium to patients in intensive care units has resulted in prolonged
neuromuscular blockade (up to several days), possibly from accumulation of its active 3-hydroxy
metabolite, changing drug clearance, or the development of a polyneuropathy
•Rocuronium (0.9–1.2 mg/kg) has an onset of action that approaches succinylcholine (60–90 s),
making it a suitable alternative for rapid-sequence inductions, but at the cost of a much longer
duration of action.

6. History of neuromuscular blocking
agents
• Early 1800’s – curare • 1942 – curare used for
discovered in use by muscular relaxation in
South American general anesthesia
Indians as arrow • 1949 – gallamine
poison discovered as a
• 1932 – West substitute for curare
employed curare in • 1964 – more potent
patients with tetanus drug pancuronium
and spastic disorders synthesized

7. Bloqueadores Não-despolarizantes
Curares - Chondrodendron e Strychnos
Farmacologia – Texto e atlas, 4ª ed., 2003.
Strychnos toxifera

8. West 1932

9. Milestones of Neuromuscular
Blockade in Anesthesia
• 1942 introduction of dTc in anesthesia
• 1949 Succinylcholine, gallamine metocurine introduced
• 1958 Monitoring of NMF with nerve stimulators
• 1968 Pancuronium
• 1971 introduction of TOF
• 1982 Vecuronium,Pipecurium,atracurium
• 1992 Mivacurium
• 1994 Rocuronium
• 1996 Cisatracurium
• 2000 Rapacurium introduced and removed

10. Aspectos Morfológicos e Funcionais

11. Aspectos Morfológicos e Funcionais
Imagem da junção Sinapse neuromuscular imagem
em microscopia eletrônica
neuromuscular em varredura

21. Canais Voltagem Dependentes

23. α 2βγδ (embrionário)
α 2βεδ (maduro)
Only the two identical α subunits
are capable of binding ACh
molecules

24. Neuromuscular Physiology
Acetylcholine receptor channels
Extrajunctional
Junctional
Anesthesia 5th ed p 740

26. Bloqueadores Não-despolarizante
MECANISMO DE AÇÃO
Tubocurarine
Potenciais de ação e potenciais de placa terminal na
vigência de bloqueador não-despolarizante

27. Bloqueadores Não-despolarizante
Margem de Segurança da Transmissão Neuromuscular

29. Site of Action of d-Tubocurarine
Nerve AP
Muscle AP
Left Leg
Muscle
Stimulation
Right Leg
Nerve
Stimulation
Right Leg Muscle Stimulation

30. Non-depolarizing Block
Bersot,CDA UFRJ

31. Bloqueadores Despolarizantes
succinilcolina

32. Bersot,cda ufrj 2002

34. Farmacologia da Junção Neuromuscular
Bloqueadores Não-despolarizantes
COMPOSTOS SINTÉTICOS
Derivados Isoquinolínicos
Lee, (2003) Pharmacology & Therapeutics, 98:143-169

35. Farmacologia da Junção Neuromuscular
Bloqueadores Não-despolarizantes
COMPOSTOS SINTÉTICOS
Derivados Aminoesteróides
Lee, (2003) Pharmacology & Therapeutics, 98:143-169

36. Farmacologia da Junção Neuromuscular
Bloqueadores Despolarizantes
Paton & Zaimis, 1949 – Decametônio e Succinilcolina
Lee, (2003) Pharmacology & Therapeutics, 98:143-169

37. Succinylcholine
“Except when used for emergency tracheal
intubation or in instances in clinical practice
where immediate securing of the airway is
necessary, succinylcholine is contraindicated in
children and adolescent patients.”

38. Succinylcholine
Advantages Disadvantages
Rapid onset Hyperkalemia
(burns,massive
trauma,denervation.…)
Short Duration
I.M. injection Cardiac Dysrhythmias
Masseter Spasm
Malignant Hyperthermia
Myalgias
Prolonged effect

39. Succinylcholine:
Hyperkalemic Response
Major burns, Massive trauma, Denervation injuries
prolonged immobility, sepsis.
– normal response; approx. 0.5 mEq/L
– not attenuated by defasciculation
– increased extrajunctional receptors (few days to form)

41. Succinylcholine:
Myalgias
• mechanism-speculative
• incidence: 0.2-89%
• young, female, early ambulation
• severity not related to intensity of fasciculations
• Pre-treatment with NDMR prevents fasciculations
and may decrease myalgias

42. Succinylcholine:
increased intragastric pressure
– G-E junction opens at pressures > 28cm H20
– transient increase up to 40 cm H20
– Defasciculate, abolishes the rise

43. Succinylcholine:
intraocular pressure
– Prevention: defasciculate, benzodiazepam,
lidocaine,acetazolamide, deep anesth. at laryngoscopy
– Drug of Choice? for the “Glaucoma” and “full stomach”
– Recommendations: SUX if possible, priorize, Airway first.
– If SUX is used: sedate and defasciculate
– transient increase of 8mm Hg ; peaks at 2-4 min
– due to contraction of extra-ocular muscles
• See Vachon C. Succinylcholine and the open globe: Tracing the
Teaching Anesthesiol 99: 220-223, 2003

44. Succinylcholine:
Prolonged Apnea after….
• Etiology
• Diagnosis
• Management

45. Prolonged Apnea after Succinylcholine
Etiology
• Decreased Plasma Cholinesterase
Activity
– Physiologic Variation
– Disease States
– Iatrogenic
– Genetic

46. Duration of Sux induced NM-block VS pChE activity
Anesthesia 5th ed p 420

47. Plasma Cholinesterase
(Prolonged Apnea after….)
• Disease States
– Hepatic Cirrhosis (reduced 50%)
– renal disease (50%), returns to normal after renal transplant
– malignancy (bronchogenic, GI)
– Burns

48. Plasma Cholinesterase
(Prolonged Apnea after…)
• Iatrogenic
– echthiophate
– anticholinesterases
– pancuronium
– pheneizine (MAO inhibitor)
– glucocorticoids (estrogens)
– organophosphates (insecticides)
– cytotoxic drugs (cyclophosphamide)

49. Malignant Hyperthermia
(Hyperpyrexia)
• Condition caused by a defect in the molecule
linking muscle membrane t-tubules to the
sarcoplasmic reticulum (ryanodine receptor).
• Uncontrolled Ca++ release from the S.R. leads to
contracture and a rise in body core temperature.
• Succinylcholine can precipitate an attack even in
the absence of halothane like anesthetics.
• Dantrolene blocks this inappropriate response of
the ryanodine receptor and prevents Ca++ loss

50. Muscle Relaxants:
Physio-chemical Properties
Highly Ionized at Physiol. pH
– + charged quaternary N attracted to
- charged cholinergic receptor
– most contain 2 + charges (biquaternary) separated by
varying sizes of lipophilic bridge (potency)
– quaternary ammonium (like Ach)

51. Muscle Relaxants:
Physio-chemical Properties
Highly Water Soluble/ Relatively Hydrophilic
– easily excreted in urine
– do not cross lipid membranes (most cells, BBB,
placenta)
– small volume of distribution
– not actively metabolized by the liver
(cytochrome P-450 enzyme system requires lipophilic
substrates)

52. Pancuronium
• Bis-quaternary Aminosteroid
• High potency therefore slow onset
• Long acting
• No or slight increase on blood pressure
• Vagolytic
• Renal clearance

53. Rocuronium
Mono-quaternary aminosteroid
– potency, approx 1/6 that of Vecuronium
– fast onset (< I min with 0.8 mg/kg)
– intermediate duration (44 min with 0.8 mg/kg)
– minimal CV side effects
– onset and duration prolonged in elderly
– slight decrease in elimination in RF

54. Mivacurium
Bisquaternary benzylisoquinoline
– potency, 1/3 that of atracurium
– relatively slow onset 1.5 min with 0.25 mg/kg
– short duration 12-18 min with 0.25 mg/kg
– histamine release with doses 3-4X ED95
– hydrolyzed by pChE, recovery may be prolonged in
some populations (e.g. atypical pChE)

55. Cis-Atracurium
one of the stereo isomers of atracurium (15%)
– 3 X more potent than atracurium
– slow onset, intermediate duration
– eliminated by Hoffman degradation
– Laudanosine as a metabolite
– non-organ elimination
– doses of 5 X ED95 (0.05mg/kg)
• no histamine release
• CV stability

56. Rapacuronium
monoquaternary aminosteroid, analogue of
Vecuronium
– low potency, fast onset, short to intermediate
duration
– 1.5-2.0 mg/kg doses give good intubating conditions
at 60 sec
– duration of action, dependent on dosage and age of
patient
– 20 % decrease in aBP observed with 2-3 mg/kg
doses
– principle route of elimination may be liver as 22% is
renal excretion.
– introduced in 2000 in US and removed, after
paediatric deaths (bronchospasm).

58. Hemodynamic Effects of d-Tubocurarine and Pancuronium
HR CO
SVR MAP

59. Effect of Potency on Onset of NMB

60. Effect of Dose on Onset of NMB

61. Hepato-Biliary Disease
Pancuronium (20% metabolized to active metabolite)
increased Vd
decreased plasma clearance
prolonged elimination T1/2
A large initial dose is required to prod the same plasma conc. but
the block will be prolonged
Vecuronium (20-30%metabolized to active metabolite)
initial studies yielded similar results to pancuronium
later studies show effect only with large doses
Rocuronium is excreted unchanged in the urine and bile. Biliary
excretion (2/3) appears to the predominant route. In cirrhotic
patients, rocuronium pharmacodynamics and elimination kinetics
are not changed much. The prolonged onset and slightly
prolonged recovery is explained by the larger Vd in these
patients.

62. Percent of Dose Dependant
on Renal Elimination
> 90% 60-90% 40-60% <25%
Gallamine (97) Pancuronium (80) d-TC (45) Succinylcholine
Pipecuronium (70) Vecuronium (20)
Doxacurium (70) Atracurium (NS)
Metocurine (60) Mivacurium (NS)
Rocuronium

63. Rationale Choice of Muscle
Relaxant:
Cardiovascular Effects
Tachycardia
Bradycardia
Hypotension
Arrhythmias

64. Reversal of Neuromuscular
Blockade
How?
• Anticholinesterases:
– Edrophonium
– Neostigmine
• Cholinesterase
• Removal of blocking agents
– Org 25969 (Cylcodextrin)
• Ring of sugars that soak up Rocuronium
•

65. Anticholinesterases
Unwanted side effects
– Autonomic
– Nausea and vomiting
• Neostigmine > Edrophonium ?
• Edrophonium (0.5-1.0 mg/kg) with Atropine ( 7-15
ug/kg)
• Neostigmine (40-70 ug/kg) with Glycopyrolate
(0.7-1.0mg)

66. Difficulty reversing block
• Right dose?
• Intensity of block to be reversed?
• Choice of relaxant?
• Age of patient?
• Acid-base and electrolyte status?
• Temperature?
• Other drugs?

67. Cold patients-longer durations
Anesthesia 5th ed p 463

68. POSTOPERATIVE RESIDUAL CURARIZATION
( PORC)
• common after NDMRs
• long acting > intermediate > short acting
• Assoc with respir. morbidity
• not observed in children
• monitoring decreases incidence

69. • Ventilatory response to hypoxia is impaired and does
not return to normal until TOF > 0.9
(Ericksson et al, Anesthesiology 78: 693-699 1993)
• Reduced Pharyngeal muscle coordination with TOF
0.6-.08
(Ericksson et al, Anesthesiology 87: 1035-43 1997)

71. Neuromuscular Transmission

72. Approximate Relationships of %
receptor blockade, ST and TOF
with NDMB
Total receptors Single twitch, T1 Train of Four, T4 T4/T1
Blocked % % normal % Normal
100 0 0
90-95 0 0 T1 lost
85-90 10 0 T2 lost
20 0 T3 lost
80-85 25 0 T4 lost
80-90 48-58 0.6-0.7
95 69-79 0.7-0.75
75 100 75-100 0.75-1.0
100 100 0.9-1.0
50 100 100 1.0
25 100 100 1.0

73. Monitoring Neuromuscular
Function
• Visual/tactile assessment of evoked
responses
• Measurement of evoked responses
• Mechanomyography
• Electromyography
• Accelerometry

74. Monitoring Neuromuscular
Function
• Mechanomyography
– Gold standard

75. Monitoring Neuromuscular
Function
• Accelerometry

77. Monitoring Neuromuscular
Function
SUPRAMAXIMAL STIMULATION
– 10-20% above current output required to stimulate all nerve
fibers
– Minimizes influence of :temp.skin resistance and changes in
electrode conductance

78. Monitoring Neuromuscular
Function
• STIMULATION PATTERNS
• Single Impulse or Twitch (ST)
• Train of Four (TOF)
• Tetanus
• Double Burst Simulation (DBS)
• Post Tetantic Count (PTC)

79. STIMULATION
PATTERNS
• SINGLE TWITCH
– Onset, dependency on frequency
– Recovery
• Control required
• May still have residual paralysis

80. STIMULATION
PATTERNS
• TETANUS
– 50 Hz, fade with NDMR’s
– 100 Hz, fade without NDMR’s
– Sensitive indicator of residual block

81. SIMULATION PATTERNS
• TRAIN OF FOUR (TOF)
– Measures continued relaxation
– Identifies phase II block
– No control required
– Tolerable in awake patients
– measurement O.7 of o.9 or
1 ????

82. STMULATION PATTERNS
• DOUBLE BURST STIMULATION
– Two bursts of 50Hz stimulation, separated by
750msec
– Measured fade correlates with TOF
– Tactile and visual evaluation of response superior to
TOF

83. STIMULATION PATTERNS
• POST TETANIC COUNT
– 50 Hz for 5 sec, followed in 3 sec by ST@ 1 Hz
– Shouldn’t be repeated more than 6 mins
– Used to monitor intense block
– Predicts optimal time to reversal