Neuromuscular blocking agents - Dr Dhir.ppt

neuro muscular agents

1. Overview
•Introduction
•Brief history
•Anatomy & physiology
•Acetylcholine (Ach) receptors
•Rapid sequence induction
•Depolarizing & Non-depolarizing agents
•Monitoring of neuromuscular block

2. Acetylcholine

4. Synthesis & storage
Mobilization
Release

5. Physiology

6. K
+
Na
+
Ca
2+
Inhibited Ca+ influx:
• Magnesium
• Ca. channel antagonists
• Aminoglycosides

7. Ca
+

8. Events
PRESYNAPTIC
•Na
+
, K
+
, & Ca
+
currents
•Ca
+
influx & vesicle exocytosis
•Ach release
CLEFT
•Ach diffusion in the cleft
•Binding to cholinesterase & hydrolysis
•Binding to Ach receptors

9. Events
POSTSYNAPTIC
•Ach binding to Ach receptors
•Channel gating
•Inward current through AChR channels
•Charging memb. capacitance
•Na
+
& K
+
currents
•Action potential propagation
•Excitation – contraction coupling

10. Muscle Nicotinic AChR
•Extended gene family (neuronal nicotinic,
GABA, glycine & 5-HT
3 receptors)
•5 subunits arranged in a donut with gated
ion channel in the middle
•Channel gating dependent on membrane
potential
•Selective for cations
•Constant state of transition (resting vs
desensitized state)

11. Muscle Nicotinic AChR
•Early development: entire muscle memb.
contains immature (extra junctional)
receptors.
•With innervation, receptors accumulate at
NMJ end plate (mature or junctional)
•Maturation is due to replacement of
gamma subunit with epsilon subunit

12. Nicotinic Receptor at adult NMJ
ACh
Alpha
Alpha
Epsilon / Gamma
Delta
Beta
Ion Channel
ACh
In fetal & denervated receptors: Gamma replaces Epsilon

13. Sodium channel
Na
= V
= T
Resting Active Inactive

14. Sodium channel
Na
= V
= T
Resting Active Inactive

15. Sodium channel
Na
= V
= T
Resting Active Inactive

16. Ach Receptors
Immature
•Spread
•Unstable
•½ life 24 hrs
•Longer burst duration
•Smaller conductance
•2-10 times longer channel
opening (slow closing)
Mature
•Localized
•Stable
•½ life 2 weeks
•Burst activity
•Normal conductance
•Channel opens for 0.5
millisecond

17. Extra junctional AChRs
•Normally suppressed by neural activity
•When nerve activity is reduced (trauma, skeletal
muscle denervation), they proliferate rapidly &
spread over entire post junctional membrane
•Highly sensitive to agonists (Ach & SCh)
•Degraded soon after neural influence returns
•Mixture of junctional & extra junctional receptors
in different clinical situations

18. Pre-synaptic AChRs
•Different strains of only
alpha and beta units
•Feedback for Ach
mobilization & release
during high frequency (>
2 Hz)
•Nicotinic = +ve feedback
•Muscarinic = -ve
feedback
•Blocked by non
depolarizing NMB agents
(fade)

19. CNS AChR
•Different subunit composition
•All contain Alpha subunits
Central effects seen after:
Prolonged use, metabolites
Disrupted BBB
Intrathecal
High specificity to Alpha
1 subunit which is exclusive
to NMJ AChR

20. Margin of safety
•10 % receptors must be open for muscle
action potential generation
•75 % receptors can be occupied before
fade is observed
•95 % receptor occupancy required for
complete twitch suppression

21. Up & Down-regulation of AChRs
UMN lesions
LMN lesions
Muscle trauma
Burn injury
Immobilization
Sepsis
Normal
Myasthenia
Organophosphates
Cholinesterase inhibition
“Up-regulation”
Increased requirement
for non-depolarizing
Agents (resistance)
Hyperkalemia after SCh
Receptor unaltered
“Down-regulation”
Reduced requirements
For non-depolarizers

22. AChR blocking agents
Non competitive
•Local anesthetics,
depolarizing agents,
Acetylcholine
•Plug the channel &
prevent ion
movement
Competitive
•Non-depolarizing
agents
•Block of one or both
Ach binding sites
•Affinity more at alpha-
epsilon site

23. Non-competitive mechanisms of
neuromuscular block
Depolarizing agents
Acetylcholine, Succinylcholine
Desensitization block
Inhalational, Thiopentone, Local anesthetics
Ion-channel block
1.Closed: TCA, Naltrexone, Naloxone
2.Open: High conc. of NMB

26. Autonomic effects
•Autonomic ganglia (nicotinic) & post
ganglionic parasympathetic (muscarinic)
receptors
•Succinylcholine: salivary secretions,
bradycardia
•d-Tubocurarine - ganglionic blockade
•Pancuronium - vagolysis

27. Histamine Release
•True anaphylaxis: Antigen / Antibody (IgE)
•Complement activation (IgG or IgM)
•Direct action on mast cell surface –
tachyphylaxis
•Prophylactic H
1
& H
2
receptor blockers
suppress

28. Anaphylactic Reactions
•Rare
•Females
•Casual relationship with cosmetics &
cleaning agents (quaternary ammonium)
•3 times common with Succinylcholine
•Cross sensitivity (mono quaternary e.g.
Vec & Roc are less likely to cause)

29. Pharmacologic variables
Definitions


Onset
0
100
25
50
75
Recovery
Index
Time to 25 % recovery
Time to 95 % recovery

30. Muscle responses
•More receptors in fast (glottis) than slow
(adductor pollicis) muscle fibres
•Rapid onset at glottis muscles is due to rapid
equilibrium (more blood flow)
•Dose required for diaphragmatic block is twice
the dose required for similar block @ adductor
pollicis
•Sequence of onset: small muscles (eyes, digits)
 trunk & abdomen  diaphragm

31. Absorption & distribution
Oral
•not absorbed
IV
•rapid onset, fast distribution & predictable
elimination
S/C or IM
•unpredictable absorption, high dose required,
only in laryngospasm without iv line
• Succinylcholine – rapid & effective absorption

32. Pharmacokinetics
Vol. of distribution:
•+ve charged quaternary ammonium
compounds remain ionized  water
soluble – Vd = ECF (0.2 – 0.5 L / Kg)
•Prolonged use - Vd increases up to 10 fold
Protein binding
•Albumin & Gamma globulins

33. Pharmacokinetics
Potency
•Low affinity – high dose – quick onset
•High affinity – small dose – slow onset
Speed of onset
•Fast injection – high gradient – quick onset
Perfusion
•Delayed onset with reduced cardiac output
•Regional blood flow.
•Onset  diaphragm < larynx < orbicularis oculi
< adductor pollicis

34. Pharmacokinetics
Obesity
•+ve charge prevents fat absorption
•Vd / kg and clearance markedly reduced
•Unaltered elimination half life
Temperature
•Prolonged action with hypothermia
•Slowed Hoffman elimination
•Temp. independent degradation of Mivacr.

35. Pharmacokinetics
Age
Children:
•Larger Vd (more dose required)
•Sensitive NMJ (prolonged action)
•Higher HR & CI (faster onset)
Aged:
•Widening of NMJ & reduced no. of receptors
•Delayed distribution & elimination
•Organ-dependent metabolism & elimination of
steroid relaxants are affected

36. Pharmacokinetics
Pregnancy
•Unaltered
•Magnesium – increased potency &
duration of action
•Ionized state – minimal placental transfer
(except prolonged use in ICU)
•May have reduced plasma cholinesterase
activity

37. Pharmacokinetics
Burns
•Up-regulation of receptors (at least 30% burns)
•Resistance to non-depolarizers (starts at10 –
peaks at 40 – declines at 60 days.)
•Altered affinity no increase in extra junctional
receptors
•Sensitive to Succinylcholine (hyperkalemia)
•Reduced plasma cholinesterase

38. Pharmacokinetics
Gender
•Women require 22% less Vecuronium
•Women 30% more sensitive to Roc
•Probably due to differences in body
composition, % of skeletal muscle mass,
Vd & Plasma protein composition

39. Elimination
•Single dose: primarily redistribution
•Multiple doses: primarily by elimination
•Renal
•All agents can be eliminated
•Normal renal function: 1-2 ml/kg/min of drug
elimination (= normal GFR)
• No re-absorption
•Poor renal function: Prolonged elimination ½ life
of renal dependent drugs (Panc, Alcuronium)

40. Metabolism
Ester hydrolysis
Plasma (pseudo) cholinesterase = E
1
u
•Succinylcholine & Mivacurium
•Dibucaine number: Normal = 70%
Dibucaine resistant = Atypical (E
1
a
)
•Heterozygous: 1:480 (DN = 35-65 %)
•Homozygous: 1:3200 (DN < 30 %)
Fluoride resistant = E
1
f

Silent = E
1
s

41. Acquired cholinesterase deficiency
Conditions:
•Liver failure
•Renal insufficiency
•Burn injury
•Pregnancy (high
estrogen levels)
Inhibitory drugs:
•Anti cholinesterases
•Pancuronium
•Metoclopramide
•Anti asthmatic drugs
•Insecticides
•Drugs for Glaucoma,
myasthenia
•Chemotherapeutic agents

42. Non enzymatic Decay
Hofmann elimination
•Atracurium & cis-atracurium
•Spontaneous degradation
•Inactive metabolites: Laudanosine and
Monocrylate
•Atracurium: ester hydrolysis

43. Hepatic elimination
•Hepatic elimination imp. in renal failure
•Steroids: Rocuronium, Pancr, Vecr.
•Deacetylation causes active metabolites
(Accumulation with prolonged use)

44. Drug Metabolism Renal Biliary
Succinylcholine98 - 99 % < 2 % --
Mivacurium 95 – 99 % < 5 % --
Atracurium 70 – 90 % 10 – 30 % Laudanosin
Cis-atracurium70 – 90 % 10 – 30 % Laudanosin
Vecuronium 30 – 40 %
(Hepatic)
40 %
(metabolites)
10 – 20 %
(metabolites)
Pancuronium 10 – 20 %
(Hepatic)
60 – 80 % 10 %
Rocuronium Minimal
(Hepatic)
30 – 40 % 60 %

45. Succinylcholine
1951
•The only depolarizing NMBA currently used
•Only NMBA with short onset (< 1 min) & short
duration (5 – 10 min)
•Both N
2 atoms are quaternary (+ ve)
•Almost exclusively used for RSI or to counteract
laryngospasm (0.1 mg/kg)
•IV injection – small fraction reaches NMJ
•ED
95 is 0.35 – 0.5 mg/kg (dose = 1mg/kg)
•Depolarizing effect within 20-40 sec
(fasciculations) followed by relaxation (< 60 sec)

49. Succinylcholine
phase II block
•Repeated boluses (infusion) of SCh
•May occur with single dose in E
1
a
•Fade, post tetanic facilitation
•Memb. potential returns to resting state
despite presence of the drug and the
transmission is blocked
•Possibly due to pre synaptic block,
aggravated by inhalational agents

50. Succinylcholine
contraindications
•Neuromuscular disease
•Denervation (after 2 days)
•Immobilization (after 3 days)
•Burns (after 2 days)
•MH susceptibility
•Homozygous for E
1
a
•Basal sr. K > 5.5
•Sepsis / infection
•Allergy to SCh

51. Dose of Succinylcholine ?
•With 1 mg / kg , block lasts 8 min.
•With preoxygenation, desaturation in 8 min.
•Some patients will desaturate
Benumof et al. Anesthesiology 1997; 87: 979

52. When to intubate ?
•Corrugator Supercilli parallels laryngeal
Adductors (not Adductor pollicis)
Plaud et al. Anesthesiology 2001; 95: 96
•Time to block is shorter with succunylcholine (1
min vs 1.5 - 2 min)
Le orre et al. A & A 1999; 89: 1305

53. Precurarization
Appropriate doses = 1 / 10 ED
95

As effective as dTC:
•Gallamine 0.2 mg / kg
(15 mg)
•Atracurium 0.025 mg /
kg (2 mg)
•Rocuronium 0.03 mg /
kg (2.5 mg)
Less effective than dTC:
•Vecuronium 0.005 mg
/ kg (0.3 mg)
•Pancuronium 0.007
mg / kg (0.5 mg)
•Mivacurium 0.01 mg /
kg (0.7 mg)
•Cisatracurium 0.005
mg / kg (0.3 mg)
Succinylcholine dose should be doubled

54. Rapid Sequence Induction
Alternatives to SCh
•Deepening level of anesthesia
•Non-depolarizing agent:
1.Priming
2.Increased dose
(CV side effects, prolonged duration)

55. Low Cardiac output and
Hypovolemia
•Slow onset (Later peak)
•Larger and broader concentration
•Improving CO (Ephedrine) can decrease
the onset time for the given dose

56. Non-depolarizing agents
•Bind to one or both Alpha units of AChRs
•Competitive antagonism of Ach
•No conformational change in AChR
•Dynamic binding (repeated association &
dissociation) – competition
•Presynaptic receptors also blocked
•70 – 80 % receptor occupancy - twitch
depression
•92 % receptor block: complete block

57. Non-depolarizing agents
Aminosteroids
•Pancuronium
•Vecuronium
•Rocuronium
•Rapacuronium
Benzylisoquinolines
•Atracurium
•Cis-atracurium
•Mivacurium
•d - Tubocurarine

58. Non-depolarizing agents
Altered response
Volatile Anesthetics
•CNS depression  reduced skeletal tone
•Decreased sensitivity of post junctional
memb. to depolarization
•No effect on Ach release or on receptors
•Change in pharmacodynamics than
pharmacokinetics
•Longer acting NMB agents affected more

59. Non-depolarizing agents
Altered response
Antibiotics
•Aminoglycosides: pre junctional effects
like magnesium (decreased release of
Ach)
•Stabilize post junctional memb.
•Calcium improves Ach release but
stabilize pos tjunctional memb, so
unpredictable effect

60. Non-depolarizing agents
Altered response
Local Anesthetics
•Enhance the block by interfering Ach
release, stabilizing memb & depressing
skeletal muscle fibres.
•Esters compete with SCh for plasma
cholinesterase activity

61. Non-depolarizing agents
Altered response
Anti dysrhythmic drugs
•IV lidocaine & quinidine potentiate the block
Diuretics
•Furosemide 1 mg/kg enhances the block
(reduced cAMP production) while large doses
inhibit PDE (increased cAMP) and antagonise
the block
•Hypokalemia decreases doses of Pancuronium
•No effect of Mannitol

62. Non-depolarizing agents
Altered response
Magnesium
•Enhanced block by reduced Ach release and
stabilizing the memb.
•SCh effect also enhanced (? Phase II block)
Lithium
•Enhanced block
Phenytoin
•Resistance to non-depolarizing NMBA

63. Non-depolarizing agents
Altered response
Steroids
•IV steroids -- no effect
•In myasthenia, ACTH or cortisol improve
NM function
Hypothermia
•Prolonged duration of action (Panc, Vec)
•Reduced hepatic, renal & Hoffman
clearance

64. Non-depolarizing agents
Altered response
Potassium
•Acute fall in extra cellular K
+
 Increased
trans memb. potential  hyper
polarization  increased sensitivity to
non-depolarizing & resistance to SCh
Paresis / Hemiplegia
•Resistance to non-depolarizers plegic limb
> healthy limb > normal individual
(Proliferation of extra junctional receptors)

65. SCh followed by a non-depolarizing
NMB agent
•Enhanced twitch suppression with
intubating dose of SCh (not with 0.5
mg/kg)
•Desensitized post junctional memb. by
SCh
•Duration of action of subsequent doses is
not prolonged

66. Combination of Non depolarizing
NMB agents
•Additive effects with drugs having same
site of action (dTc + Metocurine)
•Synergistic effects with drugs having
different sites of action (Pancuronium +
dTc or Metocurine)
oShorter duration of action
oFewer side effects

67. ED
95PrimingIntubati
ng dose
OnsetDur
25TOF>
0.9
Recov
ery
Rap
acu
1-1.2 1.5 1-1.515-2025-50
Roc.0.3 -- 0.6-11.5-2.535-5055-8060-120
Vec.0.060.01 0.15-22-3 30-4050-8090-180
Pan.0.07 3.5-670-120130-
220
Miva0.080.02 0.25 2.5-4.515-2025-4025-40
Atra.0.250.05 .7-.82-3 35-5055-8060-90
Cis-
atra.
0.050.01 .2-.43-6 40-5560-9075-120
Nondepolarizing muscle relaxants

68. Rocuronium
Mono quaternary amminosteroid
•ED
95
= 0.3 mg/kg, onset = 1 - 2 min and
duration 20 - 35 min
•Resembles Vec but less potent (fast onset)
•3-4 X ED
95
onset comparable with SCh (@
adductor pollicis & not @ larynx)
•Largely excreted unchanged (upto 50%) in bile in
2 hrs (>30% renal excretion in 24 hrs)
•Prolonged action in renal, hepatic diseases and
old age
•Absence of histamine release
•Slight vagolytic action

69. Cis-atracurium
benzylisoquinolinium
•Purified form of one of 10 steroisomers of atracurium, 5
times more potent
•Similar to atracurium except slow onset, very little
histamine & 1/5
th
less laudanosine (cerebral excitatory)
•ED95 = 50 mcg/kg, onset 3 - 5 min & duration 20 – 35
min
•77% Hoffman degradation at normal pH to inactive
laudanosine + alcohol (again Hoffman)
•17% renal clearance (non specific esterases not
involved)
•Stable hemodynamics, organ independent clearance

70. Mivacurium
Benzylisoquinoline
•Only non-depolarizer with short duration
•ED
95 80 mcg/kg, onset 2 – 3 min, duration 12 –
20 min
•2 X ED
95
ok but 3 X ED
95
 histamine release
and hypotension
•Hydrolyzed by plasma cholinesterase (88 % rate
of SCh) 7% unchanged in urine
•Inactive metabolites
•Antagonism: Spontaneous recovery, ? Reversal
with neostigmine, Edrophonium for deep block

71. Rapacurium
•Introduced in USA in 2000
•Less potent  more dose  rapid onset
•Short duration
•Histamine release  bronchospasm,
hypotension, tachycardia
•Withdrawn in 2001

72. Doxacurium
•Benzylisoquinoline
•Most recent
•Available in the USA
•Intubating dose = 0.5 mg / kg
•Long onset & prolonged duration
•No histamine release
•No cardiovascular effects
•Excreted mainly in the urine & the bile

73. Newer Agents
ORG 9487
•Aminosteroid
•Low potency, ED
90 = 1.15 mg/kg
•Rapid onset (similar to SCh @ add.pollicis but
vocal cords are resistant)
•Duration longer than SCh
BW 785 U
•Benzylisoquinolin, onset 60 – 90 sec, duration
10 – 15 min
•Histamine release  hypotension

74. Newer Agents
Gantacurium (GW 280430 A)
•By GSK, similar to Mivacurium
•ED 95 = 0.18 mg/kg
•3 x ED 95 (0.54 mg/kg): Onset 1.2 - 1.8
min & duration of 15 min
•Higher doses cause histamine release
without change in onset time
•Alkaline hydrolysis in plasma +
spontaneous formation of cysteine
adducts
•Very little genetic variability

75. Newer agents
51W89
•One of 10 isomers of Atracurium
•Onset & duration like Atracurium
•Minimum CV effects, Hofmann elimination
•“Nearly ideal” relaxant with intermediate duration
Future possibilities
•Incorporation of reversing molecule
•Reversal by complex formation (Poly anions)
•Reversal by enzymatic hydrolysis

76. Monitoring
•Time of intubation
•Degree of relaxation
•Time to reverse
•Time for extubation
•Residual curarization

77. Monitoring
Indications
•Long interventions
•Changed pharmacokinetics / dynamics
•No moving / straining allowed
•No reversal preferred
•Disturbed electrolyte balance
•Expected drug interactions

78. Monitoring
Features
•Increased safety
•Cost effective
•Easy documentation
Techniques
•Peripheral nerve stimulation (PNS)
•Mechanomyograph (MMG)
•Electromyograph (EMG)
•Acceleromyography (AMG)

79. Monitoring
Peripheral nerve stimulus
Subjective monitoring:
•Visual & / or tactile
•Muscle monitored should be in sight
•Lacks accuracy & reliability
•Acceptable TOF ratio of > 70% for extubation
(only 10% correct observations)
•Double burst stimulus (DBS): Only 40 % of
anesthesiologists are able to recognize a fade

80. Monitoring
Mechano-myograph
•Isometric measurement of force of
contraction with a force displacement
transducer.
•Simple, accurate & reliable.
•Sensitive to external physical influences
and limb has to be fixed in one position.
•Used for scientific studies

81. Monitoring
Electromyography
•Measures evoked compound muscle
action potential
•Correct positioning of electrodes very imp.
•Extensive & sensitive equipment
•Diathermy interference
•Seems to underestimate block during
recovery
•Scientific use but not popular for routine
clinical use

82. Monitoring
Acceleromyography
•Newton’s second law (F = M x a)
•Transducer is easily placed but must move
freely for reliable measurement

83. Stimulating patterns
Single twitch (ST)
•Reflects events at post junctional membrane
•Single supra maximal electrical stimuli applied to
peripheral motor nerve
•Frequency every second (1 Hz) or every 10
seconds (0.1 Hz)
•Used for monitoring onset of block
•Same response to both groups of NMBAs
•Response influenced by position of muscle,
muscle temp.
•Calibration required before relaxation (not
suitable for day-to day clinical practice)

84. Stimulating patterns
Train of four (TOF)
•Reflects events at pre synaptic membrane
•Used successfully for onset, maintenance
& recovery of block
•Four supra maximal stimuli q 0.5 seconds
(2 Hz). May be repeated q 12 – 15
seconds
•Advantage: relative ratio of 4
th
to 1
st

response remains the same despite
changes in absolute responses

85. Stimulating patterns
Tetanus
•Normally 50 Hz for 5 sec
•Fade with non-depolarizing block
•Post-tetanic facilitation
•Painful
•May produce lasting antagonism

86. Stimulating patterns
Post-tetanic count (PTC)
•If no response with ST or TOF: block can’t be
assessed. PTC assesses the intensity of deep
block (due to facilitation).
•50 Hz tetanus for 5 sec.  3 sec. later, single
twitch at 1 Hz and count the no. of responses
•Should not be repeated for 6 min. (possible
antagonism in the muscle)
•TOF is zero at PTC of 5 (T
1
appears in 5 min if
PTC > 15 for Pancuronium)

87. Stimulating patterns
Double burst stimulation
•Two short (0.2 milliseconds) bursts of 50
Hz tetanic stimuli separated by 750
milliseconds
•DBS with 3 impulses in each of bursts
(3,3) most commonly used
•Ratio of second response to the first is
equivalent to TOF ratio
•Easily seen or felt by the anesthesiologist

88. Monitoring
Influencing factors
Choice of muscle
•Diaphragm (most resistant) > other resp, upper
airway & facial muscles > peripheral &
abdominal (least resistant)
•Adductor pollicis (hand) & Flexor hallucis brevis
(leg): sensitive (may be unreliable for intubation),
less chance of overdosing,
•Orbicularis oculi: Onset, duration & sensitivity
same as resp. muscles
•Other: Laryngeal, masseter, other facial muscles
(research purposes only)

89. Monitoring
Influencing factors
Stimulation current
•Single muscle fibre = all-or-none pattern
•Whole muscle response depends upon no.
of fibres activated
•If sufficient current  all muscle fibre will
react with maximum response. Supra-
maximal stimulus (20 – 25% above that
necessary for maximal response) to evoke
response in all muscle fibres

90. Monitoring
Clinical applications
•Onset: Orbicularis oculi  ST or TOF
•Surgical relaxation: 1 or 2 responses to
TOF = sufficient block. When intense
block required  PTC
•Recovery: TOF ratio, DBS
•Reversal: When 2 or more TOF responses
•Extubation: When TOF reaches 70 – 90 %

92. Types of block

93. Train of four (TOF)
No. of
responses
Neuromuscular
block
Muscle power
1 95 % 5 %
2 90 % 10 %
3 85 % 15 %
4 75 % 25 %

94. 100 TOF %

204 TOF COUNT 0 10 PTC 0
Light Relaxant Depth Deep
Ref. value
100
50
0 %
T
1 % = 70
T
4 / T
1 = 40/70 = 60%