muscle relaxant drugs

Muscle relaxants

2011

Dr Nigel J.N. Harper

muscle relaxant drugs

pharmacokinetics receptor interactions individual drugs special situations

renal dysfunction hepatic dysfunction extremes of age burns

ACh receptor

Nicotinic5 subunits

17 subunit genesalpha 1-10beta 1-4gammadeltaepsilon

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)

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

Hepatic failure prolongs the action of ?

atracurium rocuronium cisatracurium suxamethonium vecuronium pancuronium

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)

depolarizers non-depolarizers

benzylisoquinolium cpdsaminosteroids

monoquaternary bisquaternary bisquaternary

ATRACURIUMCISATRACURIUMMIVACURIUM

PANCURONIUMVECURONIUMROCURONIUM

SUXAMETHONIUM

Ester hydrolysis Non-specific esterases (atracurium) plasma cholinesterase (suxamethonium, mivacurium)

inherited defects reduced levels

pregnancy liver failure chronic renal failure

inhibition neostigmine pancuronium

Plasma histamine release is a characteristic of normal doses of ? mivacurium

cisatracurium rocuronium suxamethonium vecuronium atracurium

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

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

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

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

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

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

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

Atracurium 2 Hofmann degradation - 70%

temperature and pH dependent yields laudanosine and an acrylate

Hydrolysed by esterases - 30% yields a monoquaternary acid + monoquaternary

alcohol

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

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

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

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

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

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)

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

60 seconds

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

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

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

Fetal (immature) ACh receptor

Easier to depolariseHigher agonist affinityLonger channel-opening time

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

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

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

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

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

Complications of suxamethonium

Fasciculations Myalgia Bradycardia Hyperkalaemia Raised intraocular

pressure

Raised intragastric pressure

Prolonged NMB Myoglobinuria Anaphylaxis Malignant

hyperthermia

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

A decrease in plasma AChE activity can be found in association with...

thyrotoxicosis pregnancy severe burns neostigmine propranolol mivacurium

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

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

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

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

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

DBS v TOF

?

0.4

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

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

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

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

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)

When is neostigmine unnecessary?

No DBS fade Double check by ensuring

no tetanic (50 Hz) fade

When is it safe to attempt to reverse?

The second DBS twitch is easily discernible

rocuronium

sugammadex

ORG 25969 ( cyclodextrin)sugammadex

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

Sugammadex reversal recommendations

Reappearance of T2 2mg/kg PTC = 1-2 4mg/kg Immediate reversal 16mg/kg

TOF>0.9 in 1.5 mins

Methods of monitoring

Visual Tactile Mechanomyography Acceleromyography Electromyography

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