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Muscle relaxants
2011
Dr Nigel J.N. Harper
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muscle relaxant drugs
pharmacokinetics receptor interactions individual drugs special situations
renal dysfunction hepatic dysfunction extremes of age burns
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ACh receptor
Nicotinic5 subunits
17 subunit genesalpha 1-10beta 1-4gammadeltaepsilon
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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)
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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
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Hepatic failure prolongs the action of ?
atracurium rocuronium cisatracurium suxamethonium vecuronium pancuronium
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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)
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depolarizers non-depolarizers
benzylisoquinolium cpdsaminosteroids
monoquaternary bisquaternary bisquaternary
ATRACURIUMCISATRACURIUMMIVACURIUM
PANCURONIUMVECURONIUMROCURONIUM
SUXAMETHONIUM
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Ester hydrolysis Non-specific esterases (atracurium) plasma cholinesterase (suxamethonium, mivacurium)
inherited defects reduced levels
pregnancy liver failure chronic renal failure
inhibition neostigmine pancuronium
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Plasma histamine release is a characteristic of normal doses of ? mivacurium
cisatracurium rocuronium suxamethonium vecuronium atracurium
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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
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cont
rol
H1 H2H1 + H2
% c
hang
e in
MA
P
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
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cont
rol
H1 H2H1 + H2
% c
hang
e in
MA
P
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
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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
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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
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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
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Atracurium 1 10 isomers Benzylisoquinolinium compound designed to undergo Hofmann degradation pH = 3 in ampoule keep in refrigerator ED95 = 0.23 mg/kg
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Atracurium 2 Hofmann degradation - 70%
temperature and pH dependent yields laudanosine and an acrylate
Hydrolysed by esterases - 30% yields a monoquaternary acid + monoquaternary
alcohol
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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
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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
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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
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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
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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
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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)
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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
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60 seconds
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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
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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
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Maturation of theneuromuscular junction
innervation changes from polyneuronal to focal
increased myelination increased Ach release loss of extrajunctional receptors gamma subunits gradually replaced by
epsilon
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Fetal (immature) ACh receptor
Easier to depolariseHigher agonist affinityLonger channel-opening time
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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
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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
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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
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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
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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
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Complications of suxamethonium
Fasciculations Myalgia Bradycardia Hyperkalaemia Raised intraocular
pressure
Raised intragastric pressure
Prolonged NMB Myoglobinuria Anaphylaxis Malignant
hyperthermia
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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
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A decrease in plasma AChE activity can be found in association with...
thyrotoxicosis pregnancy severe burns neostigmine propranolol mivacurium
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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
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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
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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
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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
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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
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DBS v TOF
?
0.4
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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
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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
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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
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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
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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)
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When is neostigmine unnecessary?
No DBS fade Double check by ensuring
no tetanic (50 Hz) fade
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When is it safe to attempt to reverse?
The second DBS twitch is easily discernible
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rocuronium
sugammadex
ORG 25969 ( cyclodextrin)sugammadex
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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
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Sugammadex reversal recommendations
Reappearance of T2 2mg/kg PTC = 1-2 4mg/kg Immediate reversal 16mg/kg
TOF>0.9 in 1.5 mins
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Methods of monitoring
Visual Tactile Mechanomyography Acceleromyography Electromyography
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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