1. Muscle relaxants
2011
Dr Nigel J.N. Harper

2. muscle relaxant drugs
 pharmacokinetics
 receptor interactions
 individual drugs
 special situations
 renal dysfunction
 hepatic dysfunction
 extremes of age
 burns

3. ACh receptor
b
a
e
d
a
Nicotinic
5 subunits
17 subunit genes
alpha 1-10
beta 1-4
gamma
delta
epsilon

4. Protein binding
 All relaxants are protein bound
 albumin
 globulins
 alpha 1 acid glycoprotein
 value depends on method used for measurement
(30 - 90% for all relaxants)

5. Renal excretion
 All renally excreted to some extent
 may be broken down before renal
excretion becomes important (sux, atra,
miv)
 proportion of total dose recoverable in
urine:
 atracurium 11% at 6h
 vecuronium 67% at 24h
 rocuronium 33% at 24h

6. Hepatic failure prolongs the action of ?
 atracurium
 rocuronium
 cisatracurium
 suxamethonium
 vecuronium
 pancuronium

7. Hepatic uptake
 Aminosteroids largely taken up by and
metabolised in the liver (acetylated)
 more liphophilic (fewer quaternary nitrogen
groups) drugs taken up more avidly
 monoquaternary (vecuronium, rocuronium)
 bisquaternary (panc, atra, cisatra, miv)
 triquaternary (gallamine)

8. depolarizers non-depolarizers
benzylisoquinolium cpdsaminosteroids
monoquaternary bisquaternary bisquaternary
ATRACURIUM
CISATRACURIUM
MIVACURIUM
PANCURONIUMVECURONIUM
ROCURONIUM
SUXAMETHONIUM

9. Ester hydrolysis
 Non-specific esterases (atracurium)
 plasma cholinesterase (suxamethonium,
mivacurium)
 inherited defects
 reduced levels
 pregnancy
 liver failure
 chronic renal failure
 inhibition
 neostigmine
 pancuronium

10. Plasma histamine release is a
characteristic of normal doses of ?
 mivacurium
 cisatracurium
 rocuronium
 suxamethonium
 vecuronium
 atracurium

11. Histamine release & hypotension
%
change
MAP
% change
heart rate
% change
plasma
histamine
vecuronium -1.8 -0.5 -8
rocuronium -4.3 +2.8 +20
atracurium -22.5 +21.6 +134
mivacurium -23.6 +15.9 +170
Naguib M et al. Br J Anaesth 1995; 75: 588-592

12. control
H1 H2
H1 +
H2
%changeinMAP Hypotension after atracurium:
Effect of H blockade
Hosking P, Lennon RL, Gronert GA. Anesth Analg 1988; 67: 1089-1092
-40
-35
-30
-25
-20
-15
-10
-5
0

13. control
H1 H2
H1 +
H2
%changeinMAP Hypotension after atracurium
Hosking P, Lennon RL, Gronert GA. Anesth Analg 1988; 67: 1089-1092
Possible
antagonism of
H3 receptors
which
normally
inhibit the
synthesis &
release of
histamine
-40
-35
-30
-25
-20
-15
-10
-5
0

14. Mivacurium 1
 hydrolysed by plasma cholinesterase (75%
rate of suxamethonium)
 3 optical isomers
 cis-trans & trans-trans rapidly hydrolysed
(elimination half times 2.9 min & 3.6 min)
 cis-cis slowly hydrolysed (35 min)
 overall half time 5 min
 non-cumulative

15. Mivacurium 2
 Intubating dose 0.2 mg / kg
 onset time 2.5 min
 not greatly decreased by increasing the dose (law
of mass action)
 Histamine release +++
 size of dose limited by hypotension and other
histamine-related side-effects

16. Mivacurium 3
 DUR 25 = 12-15 min
 DUR 95 = 25 min
 duration not increased in the elderly or in organ
dysfunction
 Duration increased by atypical cholinesterase
 non-cumulative
 offset not greatly accelerated by neostigmine

17. Atracurium 1
 10 isomers
 Benzylisoquinolinium compound
 designed to undergo Hofmann degradation
 pH = 3 in ampoule
 keep in refrigerator
 ED95 = 0.23 mg/kg

18. Atracurium 2
 Hofmann degradation - 70%
 temperature and pH dependent
 yields laudanosine and an acrylate
 Hydrolysed by esterases - 30%
 yields a monoquaternary acid +
monoquaternary alcohol

19. laudanosine
 Remotely related to opioids
 no muscle relaxant properties
 long plasma half time
 excreted via kidney
 found in CSF when bbb damaged
 epileptogenic in dogs

20. Atracurium 3
 Onset time 3 mins
 DUR 25 = 25 min
 Histamine release common
 Contributes to hypotension on induction
 Non-cumulative
 Duration not prolonged in organ failure or
plasma cholinesterase deficiency

21. Cisatracurium 1
 Single cis-cis isomer of atracurium
 forms 15% of atracurium with 65% of the
neuromuscular blocking activity
 three times as potent as atracurium
 no histamine release
 excellent cardiovascular stability

22. Cisatracurium 2
 Degradation pathways same as atracurium
 yields less laudanosine because more potent
than atracurium
 onset time same as atracurium
 duration slightly longer
 non-cumulative

23. Rocuronium 1
 Analogue of vecuronium (aminosteroid)
 less potent than vecuronium
 more stable (presented as a solution)
 faster onset (intubation at 90 sec)
 same duration as vecuronium
 largely eliminated unchanged in bile

24. Rocuronium 2
 Duration increased ++ by hepatic dysfunction
(monoquaternary) Duration of a single bolus
not increased in renal failure
 Duration increased by 65% in the elderly (in
common with vecuronium)
 Cumulative after repeated boluses (or
infusion)

25. Intubation after suxamethonium
should be carried out as soon as
possible after
 the fasciculations have stopped
 90 seconds
 60 seconds
 the jaw has relaxed
 45 seconds

26. 60 seconds

27. On a mg/kg basis, compared with
an adult, at 3 months a child ...
 Is sensitive to suxamethonium
 is resistant to atracurium
 has more type 1 muscle fibres
 has more epsilon subunits in the ACh
receptor
 has a proportionately greater ECF volume

28. Relaxants in children
 Children are resistant to relaxants
 Maturation of the NMJ
 Changes in fast / slow fibre ratio
 proportional alteration of skeletal muscle
compartment
 Proportional change in ECF volume
 Changes in metabolism & clearance

29. Maturation of the
neuromuscular junction
 innervation changes from polyneuronal to
focal
 increased myelination
 increased Ach release
 loss of extrajunctional receptors
 gamma subunits gradually replaced by
epsilon

30. Fetal (immature) ACh receptor

b
a
e
d
a
Easier to depolarise
Higher agonist affinity
Longer channel-
opening time

31. Maturation of muscle fibres
 Conversion from slow contracting (type 1-
resistant to paralysis) to fast contracting (type
2 - paralysed more easily) fibres in peripheral
muscle
 The opposite occurs in the diaphragm

33. Changes in body compartments
 Proportion of skeletal muscle
decreases during first year
 subsequently, proportion of skeletal
muscle increases to reach a
maximum of 40%
 ECF (relaxant pool) decreases from
45% at birth to 23% in the adult

34. Immature metabolism
 Renal function not maximal until 2yrs
(measured by creatinine clearance)
 plasma clearance of atracurium greater
in infants because of larger volume of
distribution therefore duration of action
is decreased
 duration of vecuronium and rocuronium
increased in neonates and infants

35. Suxamethonium in children
 Resistant on a dose / weight basis (but not on
a dose / BSA basis)
 large volume of distribution
 double dose in neonates and infants
 increase by 20% in older children
 Shorter duration
 redistribution from a small muscle compartment to
a large ECF compartment

36. Burns (20% +)
 Resistance to non-depolarizers after 7
days (avoid sux after 4 days)
 proliferation of extra-junctional receptors
 act as a sump for relaxant molecules
 increased margin of safety
 suxamethonium produces hyperkalaemia
 all receptors subject to gamma substitution
 less avid binding of relaxants

37. Complications of suxamethonium
 Fasciculations
 Myalgia
 Bradycardia
 Hyperkalaemia
 Raised intraocular
pressure
 Raised intragastric
pressure
 Prolonged NMB
 Myoglobinuria
 Anaphylaxis
 Malignant
hyperthermia

38. Suxamethonium and hyperkalaemia
 Motor neuron defect (upper or lower) inc CIP
 Prolonged chemical denervation
 NMBA
 Magnesium
 Clostridial toxins (Botulinum/Tetani)
 Direct muscle trauma, tumour, inflammation or
thermal injury
 Disuse atrophy
 Potential hazard for 8 weeks after discharge from
ICU
 NOT steroids

39. A decrease in plasma AChE activity
can be found in association with...
 thyrotoxicosis
 pregnancy
 severe burns
 neostigmine
 propranolol
 mivacurium

41. The plasma AChE variant E1uE1a is
associated with ..
 A dibucaine number of 60
 a fluoride number of 50
 a normal duration of mivacurium
 approximately 1 in 500 of the population
 the atypical gene

43. A train of four ratio of 0.7 is
associated with ...
 the ability to breathe normally
 three twitches palpable out of four
 palpable fade of the thumb twitch in most
patients
 the need for neostigmine for reversal
 a DBS ratio of 0.7
 a post tetanic count of four

44.  A TOF ratio of 0.9 is needed to breathe
adequately
 Unless the TOF is <0.4, tactile
assessment will not reliably detect fade
 Using DBS the corresponding ratio is 0.8
 Using a transducer the TOF ratio = the
DBS ratio

45. Double burst stimulation
 Comprises two stimuli
 is useful to measure adequate reversal
 can be used to decide whether neostigmine
is needed
 is useful to decide when to intubate
 is more painful that post tetanic count

46. Double burst stimulation
 More accurate tactile fade assessment than
TOF
 two bursts of three 50Hz stimuli with a 0.75s
interval between the bursts
 can be used interchangeably with TOF but
better if tactile or visual assessment is used

47. DBS v TOF
?
0.4



48. Post tetanic count
 Is a useful guide to intubation
 is useful to decide whether a patient is fully
reversed
 comprises two tetanic stimuli
 measures profound blockade
 is high when the patient is lightly blocked

49. PTC
 5s 50Hz tet, then 3s pause, then 1Hz
 PTC = 10 when first TOF/DBS twitch
reappears
 Useful to quantify profound block
 = 3-4 to ablate carinal reflex
 interval of 30s needed between
measurements

50. Anticholinesterases
 Neostigmine and pyridostigmine binds to
AChE chemically at the esteratic site
 A carbamate-enzyme complex is formed
 The carbamate-enzyme complex is finally
hydrolysed, regenerating the active AChE

51. Anticholinesterases
 Edrophonium bonds to the anionic site of
AChE by electrostatic attachment and the
esteratic site by hydrogen bonding
 No chemical bonds are formed
 Transient effect

52. PostOperative Residual Curarization
(PORC)
 Common
 Predisposes to atelectasis
 Impaired VC and cough (exp muscles, laryngeal
adductors)
 Causes upper airway obstruction
 Reduced UOS tone and pharyngeal co-ordination
 Predisposes to Hospital Acquired Pneumonia
 Micro-aspiration (laryngeal incompetence, impaired
cough, impaired swallowing)

53. When is neostigmine unnecessary?
 No DBS fade
 Double check by
ensuring no tetanic (50
Hz) fade

54. When is it safe to attempt to
reverse?
 The second DBS twitch
is easily discernible

55. rocuronium
sugammadex
ORG 25969 ( cyclodextrin)
sugammadex

56. Sugammadex (Bridion)
 T1/2 beta 1.8 hours
 Plasma clearance 88ml/min
 >70% excreted in 6 hours
 Capturing Interaction
 Hormonal contraceptives
 Displacement interaction
 Toremifine (selective estrogen receptor modulator
used in breast and prostate cancers)
 Flucloxacillin
 Fucidic acid

57. Sugammadex reversal recommendations
 Reappearance of T2 2mg/kg
 PTC = 1-2 4mg/kg
 Immediate reversal 16mg/kg
 TOF>0.9 in 1.5 mins

58. Methods of monitoring
 Visual
 Tactile
 Mechanomyography
 Acceleromyography
 Electromyography

59. Different muscle groups
 Facial muscles resistant to NMB
 Adductor pollicis same as tibial muscles
 Onset and offset faster in laryngeal
muscles, but relatively resistant
 Ditto diaphragm
 Rocuronium paralyses laryngeal muscles
faster than other N-D NMBA