neuromuscular blocker

Question 1

classify the neuromuscular blocking agents?

Answer 1

depolarising
* non-competitive nAChR inhibition
* e.g. succinylcholine

non-depolarising
* competitive inhibition of pre and post synaptic nAChR
* 2 groups - benzyolisoquinoliniums (atracurium and mivacurium) and aminosteroids (roc, vec, pan)

Question 2

what is the need for neuromuscular blockade?

Answer 2

intubation
optimise surgical field esp in neurosurgery/ opthalmic
fascilitates ventilation.

Question 3

describe the structure and synthesis of acetylcholine..

Answer 3

acetyl co A + choline
joined by ester link
quarternary amine

packed into vesicles - 5000 Ach/ vesicle = quantum. organised into active zone/ reserve pool and stationary store.

Question 4

How many AchR need to be activated for muscle contraction, what are the implications?

Answer 4

there is a huge redunancy of AchR - only 10% need to be activated for muscle contraction.

this gives a safety margin.

however also means for paralysis >80% need to be blocked

Question 5

how does the structure of NMBA relate to ACH?

Answer 5

suc is 2x Ach molecules hence activates the receptor and is also broken down by esterases

non-depolarising - similar as they all have quarternary amine groups, which is responsible for receptor binding.

Question 6

can you give examples of when AChR are up/down regulated and what are the implications of this…

Answer 6

upregulation
- burns, spinal cord injury, guillian barre, severe sepsis, neuropathies
- usually extra junctional fetal type receptors - more sensitive and stay open for longer and result in more K+ efflux hence hyperkalaemia can result from depolarising block
- may require larger doses of non-depolarising NMBA

down regulation
- myasthenia gravis
- nicotine
- increased sensitivity to non-dep NMBA hence need less to get paralysis but reduced sensitivity to depolarising NMBA.

Question 7

which conditions that cause extrajunctional receptors should depolaring blocks be avoided ?

Answer 7

burns >10% between 24hours - 18months old

spinal cord trauma 12 hours to 18 months

muscular dystrophies

Question 8

how does myasthenia gravis effect NMBA?

Answer 8

increased sensitivity to non-dep NMBA hence need less to get paralysis but reduced sensitivity to depolarising NMBA

the treatment for MG is the use of acetylcholinesterase blockers. These also inhibit plasma cholinesterase and hence reduce breakdown of sux.

Question 9

tell me about the Vd of NMBA

Answer 9

very water soluble
relatively large
with quarternary amine

therefore not v.lipid soluble and tend to stay in water soluble compartments
therefore small Vd usually around 0.5l/kg

can be increased in conditions that increase fluid in ECF e.g. cirrhosis.
also increased Vd in neonates
in these cases the dose would need to be increased but the duration will be longer.

Question 10

what determines the termination of NMBA effects?

Answer 10

the concentration gradient between NMJ and plasma

onset - conc gradient into NMJ
offset - metabolism/ excretion lowers plasma conc so gradient is reversed and NMBA leaves NMJ

the quicker the metabolism/excretion, the quicker the drop in conc gradient and hence quicker the offset.

non depolarising - also affected by competition from ACh hence if Ach increased in cleft (neostigmine), this terminates action quicker

Question 11

how is potency of NMBA measured and what is the implications of this?

Answer 11

ED95 = dose needed to reduce the twitch height by 95% of original
smaller the ED95 - the more potent
(ED50 can also be used - for 50% of height)

recommended intubating dose is 2x ED95

The less potent, the more drug needed, steeper conc gradient, quicker onset = bowman principle e.g. rocuronium

e.g. ED95 of rocuronium = 0.3mg/kg and atracurium is 0.2mg/kg

Question 12

how is the clinical duration of a NMBA officially measured?

Answer 12

time taken from injection to recovery of 25% of original twitch height.

recovery index = recovery from 25% to 75% of twitch height.

Question 13

Describe the different TOF patterns seen in depolarising and non-depolarising agents…

Answer 13

non depolarising:
onset = fade and then loss of 4 twitches one at a time, until complete block where theres none.
off set = the reverse. when 4 twitches back and there is fade a TOF ratio can be calculated between 1st and 4th twitch. in total block, can be potentiated by post tetatanic potentiation

depolarising
onset = reduction in twitch height of all 4 but no fade. followed by complete loss of all 4
off set phase 1 block- the reverse. doesnt show fade or post tetanic potentiation
phase 2 block - when given repeatedly starts to show characteristics of non-depolarising agents e..g fade and post tetanic potentiation

Question 14

what is the mechanism behind fade?

Answer 14

there are pre-synaptic AChR
these have a role in mobilising reserve pools of vesicles to rapidly release pool to allow repeated AP to cause release.

blocking these means this process is less efficient and therefore the rapidly release pools are not replaced and less can be released hence weaker muscle response.

Question 15

when does phase 2 block occur?

Answer 15

prolonged exposure to sux i.e. repeated dose
or >2-5mg/kg odose
may see in sux apnoea patients after normal dose

Question 16

what is the mechanism behind post tetanic stimulation?

Answer 16

tetanic stimulus applied = 50mA, 50Hz, 5seconds each 0.2ms. followed by pause and then single twitches.

the tetany causes build up of ACh in NMJ to improve efficacy of normal stimulus after.

seen in non-depolarising blocks or phase 2 of a depolarising block.

Question 17

how is TOF used for intubation/ extubation guidance?

Answer 17

max 1 twitch for intubation
during surgery - depends on surgery
to give neostigmine = 2 or 3 twtiches
to extubate TOF more than 0.9

Question 18

how is TOF ratio measured?

Answer 18

height of 4th twitch / height of first twitch

Question 19

how can you reduce the myalgia seen with succinylcholine?

Answer 19

give small amount of non-depolarising agent first e.g. 0.1mg/kg roc - blocks some receptors to reduce fasciculations

or lidocaine too

Question 20

what is succinylcholine apnoea?

Answer 20

genetic condition resulting it exagerrated and prolonged effects of succinylcholine and mivacurium. various forms of the allele which result in various degrees of apnoea.

plasma cholinesterases are responsible for metabolising succinylcholine. This enzyme is encoded by gene on chromosome 3 which has various alleles within the population including…
Eu = usual
Ea = atypical
Ef = fluride resistant
Ed = dibucaine resistant
Es = silent - absent enzyme

various combinations will result in different rates of metabolic activity of this enzyme. e.g. EsEs = little / no activity and apnoea can last up to a day. whereas EuEa is reduced but only for up to 30mins.

95% of population is homozygous for EuEu which metabolises sux in 10mins.

although classically thought of as a genetic abnromalities. It can also be acquired e.g. if theres reduced production by the liver - liver failure and malnutrition. OR through DDIs for example lithium and neostigmine reduce the activity of plasma cholinesterase

Question 21

how is succinylcholine apnoea managed?

Answer 21

recognise - patient may tell you in pre op that they have previously had an issue with it OR family member. may instead only find this out after use. important to use TOF after succinylcholine and before atracurium use. otherwise at end of op, no signs of muscle activity e.g. not breathing etc.

maintain anaesthesia and ventilation
may need to be transfered to ITU
FFP can be given to provide normal pseudocholinesterase
refer for genetic testing
let them know the issue and write to GP.

Question 22

how is Sux Apnoea diagnosed?

Answer 22

dibucaine test

dibucaine is a local anaesthetic that inhibits normal alleles of plasma cholinesterases (does not inhibit abnormal alleles)
benzylcholine is a substrate for plasma cholinesterases and when it is broken down it emits light of a specific wavelength which is measure.

patients blood sample taken
benzylcholine added and light measured
next dibucaine and benzylcholine addeed and light measured.
in those with normal allele, the dibucaine inhibits the enzyme such that it doesnt break down benzylcholine and so less light emitted. There is a drop in light emission when compared to benzylcholine alone.

in those with abnormal enzyme, dibucaine doesnt inhibit the enzyme and thus the reduction in light emision is not much.

dibucaine number is the % drop in light emitted/ beznylcholine breakdown in presence of dibucaine..
75-80% is normal
in those with sux apnoea can be as low as 30%

Question 23

what is the differences in metabolism between the 2 groups of NON depolarising agents?

Answer 23

benzylisoquinoliums
* atracurium and cisatracurium = hoffmans degradation and ester hydrolysis
* mivacurium = plasma cholinesterases

aminosteroids
* hepatic metabolism + renal/bile excretion.
* monoquarternary amine - rocuronium + vec - bile excretion
* bisquarternary amine - panuronium - urinary (more effected by renal clearance than roc)
* some active metabolites produced e.g. vecuronium metabolite nearly as potent as vec, roc 20% potency

Question 24

what isomers of mivacurium exist?

Answer 24

3 isomers = geometric
cis-cis
cis-trans
trans-trans -main one

Question 25

what toxins effect the NMJ?

Answer 25

pre-synaptic * tetanus toxin from clostridium tetani = stops release of GABA and glycine. causes muscle tetany * botulinum toxin from clostridium botulinum = stops release of ACh by action on SNAREs. flaccid paralysis, dry mouth, blurred vision. * B neurotoxin from krait snake - inhibits ACh release * hemicholinium blocks uptake of choline into neurons preventing synthesis. post synaptic * a neurotoxin - from krait snake - binds nAChR irreversibly * organophosphates - irreversible inhibition of acetylcholinesterase - high levels of ACh - depolarising block effect (flaccid paralysis) + cholinergic effects (SLUDGEM)

Question 26

what are the symptoms of organophosphate poisoning?

Answer 26

flaccid paralysis - excess Ach has depolarising block effect cholinergic toxicity = SLUDGEM = salivation, lacrimation, urination, diarrhoea, GI cramping, emesis, miosis

Question 27

which NMBAs are associated with histamine release

Answer 27

benzylisoquinoliums

Question 28

how does sensitivity to NMBA vary between muscle groups?

Answer 28

paralysis after NMBA is not uniform across all muscle groups and neither is recovery. most sensitive are small muscles e..g adductor pollicis diaphragm is relatively insensitive. the reverse is also true, the diaphragm will recover quicker than adductor pollicis hence reversal of adductor pollicis brevis is a good predictor of diaphragm reversal.

Question 29

what reversal agents do you know?

Answer 29

acetylcholinesterase inhibitors * reversal of non-depolarising NMBA * work via increasing ACh for competition and hence displacement and reduced effects of NMBA. * they can actually potentiate depolarising agent suggamadex * cyclodextrin molecule that chelates rocuronium and vecuronium * rapid reversal

Question 30

what anticholinesterase inhibitors do you know?

Answer 30

can be classed into 2 groups - reversible and irreversible. reversible onces further into... short acting = edrophium - used in tensilon test for myasthenia gravis. medium = neostigmine and - carbamylation - 30mins duration (due to time for regenerating enzyme) longer acting = pyridostigmine - (used for MG treatment) irreverisble = organophosphate poisoning. (need to produce new enzyme)

Question 31

what are the side effects of anti-cholinesterase inhibitors? how is this dealt with?

Answer 31

increase in Ach is non specific so also effects parasympathetic NS bradycardia salivation, lacrimation GI upset - diarrhoea , nausea, cramping miosis bronchospasm doesnt cross BBB so doesnt have central effects often mixed with glycopyrolate which acts on mAChR - this means the effects of Ach are still seen on nACH but side effects at mACh are inhibited.

Question 32

why is atropine not used instead of glycopyrolate with neostigmine

Answer 32

both block mAchR so would reduce side effects of neostigmine however atropine less favourable because Crosses BBB so more side effects esp in elderly quicker onset and offset, so transient tachycardia before neostigmine acts and could end up being bradycardic again in recovery.

Question 33

what are the signs of inadequate reversal in recovery?

Answer 33

poorly sustained twitchy movements weak cough inability to hold head lifted risk of aspiration and hypoxia

Question 34

how can you assess NMBA reversal?

Answer 34

clinically - sustained head lift, size of tidal volume, grip strength, tongue protrusion objectively - TOF

Question 35

what is the tensilon test?

Answer 35

distinguishes myasthenia gravis from cholinergic crisis in cholinergic crisis - excess Ach can lead to depolarising block however symptoms of SLUDGEM in cholinergic arent seen in MG. tensilon test will block anticholinesterases via edroponium. if symptoms worsen this is cholinergic crisis, if better MG.

Question 36

draw a table comparing dose, potency, duration, onset and metabolism of the NMBAs.

Answer 36

Question 37

which NMBA are used in ITU?

Answer 37

atracurium and cisatracurium are preffered as not reliant on renal/liver clearance however technically risk of laudanosine building up in organ failure.

Question 38

what are the properties of an ideal NMBA?

Answer 38

physiochemical * easily prepared i.e. already constituted * long shelf life * stable at room temp and in light * compatible with plastics used and other drugs pharmacodynamics * low potency - such that bowman principle can be applied * quick onset * quick and predictable offset * no histamine release * no other side effects - painless injection , low anaphylaxis rates * reversible agent available pharmacokinetics * can be given IV or IM * independant of liver metabolism * e.g. hoffmans degradation - independant on organs/ enzymes * no active metabolites * not dependant on renal fucntion for clearance. * unable to cross placenta

Question 39

which agent is best in renal failure?

Answer 39

atracium/cisatracurium - hoffmans and ester hydrolysis roc - has active metabolites and some renal clearance + suggamadex renally cleared sux - hyperkalaemia risk

Question 40

what are the DDIs of NMBAs?

Answer 40

prolong block for non depolarising via blocking pre-synaptic Ca channels and hence ACh release... * MgSO4 * aminoglycosides * tetracyclines via muscle relaxation and synergistic effect * voltatiles * thiopentone

Question 41

how does acidaemia and hypothermia affect NMBA?

Answer 41

acidaemia and hypothermia - reduce breakdown via hoffmans acidaemia - protonation of quarternary amine - increases affinity for AchR

Question 42

how do electrolyte changes effect NMBA?

Answer 42

low Ca - less Ca for exocytosis - prolongs block low K - hyperpolarisation - prolongs block

Question 43

how does Acetylcholine activate AChR

Answer 43

binds at a subunit 2 must bind to activate nAChR

Question 44

tell me about neostigmine

Answer 44

anticholinesterase inhibitor similar structure to acetylcholine with quartnary amine works via carbmylation of the enzyme presented as 2.5mg/ml in 1ml vial and often pre-mixed with glycopyrolate (0.5mg glyco/ 2.5mg neo) used to reverse NMBA and in treatment of ileus side effects include - cholinergic efects + bradycardia + bronchospasm + PONV

Question 45

what anti-cholinesterase drugs are therapeutically?

Answer 45

neostig pyridostigmine - treatment of MG edrophonium =testing MG/cholinergic crisis

Question 46

which organophosphates do you know and how do they work as poisons?

Answer 46

insectide, nerve gas highly lipid soluble, absorbed across skin phosphorylate the esteric site of acetylcholinesterase also inhibit plasma cholinesterases results in high levels of ACh in NMJ - depolarising block, cholinergic efects and eventually apnoea and coma.

Question 47

how is organophosphate poisoning treated?

Answer 47

supportive atropine sedation and ventilation pralidoxime - promotes hydrolysis of phosphorylated acetylcholinesterase complex

Question 48

what is meant by cholinergic crisis? how is it managed?

Answer 48

The presence of excess ACh in NMJ causes overstim of AChRs SLUDGEM + paralysis + bradycardia this can occur from organophosphate poisoning or in MG patients who have had excessive amounts of their medication (pyridostigmine) In MG may need to distinguish from myasthenia crisis as both will cause weakness - use edrophonium to treat - atropine, supportive, invasive ventilation may be required

Question 49

tell me about plasma cholinesterase

Answer 49

plasma cholinesterases are enzymes present in the plasma that catalyse ester bonds. They are involved in the metabolism of various drugs including succinylcholine and mivacurium.

Question 50

tell me about plasma cholinesterase deficiency..

Answer 50

this is a reduced amount and thus activity of plasma cholinesterases it can be acquired or genetic genetic causes include sux apnoea - 4 alleles. abnormal alleles a,f,s combinations will result in reduced activity of the enzyme compared to the homozygous AuAu acquired causes can come from liver disease, malnutrition, loss of protein (severe burns, renal failure, plasmaphoresis), pregnancy, inhibition e.g. neostigmine.

Question 51

what is meant by post op residual curarisation?

Answer 51

muscle relaxant after anaesthesia associated with airway weakness, aspiration, obstruction, apnoea, hypoxia hence why NMB monitoring is required

Question 52

classify the main NMBA in terms of duration

Answer 52

short duration - mivacurium, sux medium - atracurium, roc long - pancuronium

Question 53

tell me about atracurium

Answer 53

NMBA belonging to the benzylisoquinoliums. it commonly used for elective cases at induction when RSI is not required or as maintainance NMBA after sux. it comes as a clear colourless solution for IV injection. found as 10mg/ml in 5ml or 2.5 ml ampules. stored in fridge at 4 degrees. Given as 0.5mg/kg dose at induction and takes 3-4mins to work. acts as a non-depolarising competitive antagonist of the nAChR. therefore causing flaccid paralysis through blocking this receptor from acetylcholine. pharmacodynamics - other than the intended effect of paralysis it has a number of ADRs - causes histamine release and therefore can drop BP and cause bronchospasm - avoided in asthmatics - risk of anaphylaxis - risk of ventilator associated weakness after prolonged use in ITU pharmacokinetics - IV absorption, 100% BO - charged and relatively large therefore remains in ECF so small Vd - broken down via hoffmans degradation and ester hydrolysis - 10% excreted unchanged in kidney

Question 54

how many isomers of atracurium exist? tell me about one of these

Answer 54

4 chiral centres proudcing 10 optical isomers 1= cis atracurium = cis cis stereoisomer of atracurium this is more potent than atracurium given as 0.1mg/kg undergoes more hoffman degradation (compared to ester hydrolysis) less associated with histamine release

Question 55

what is hoffmans degradation

Answer 55

spontaneous breakdown of atracurium at body temp and ph produces laudanosine as a product which is inactive and cleared by the kidneys. in accumulation laudanosine is thought to cause seizures hoffmans slows dwon by acidosis and hypothermia.

Question 56

tell me about mivacurium

Answer 56

a benzylisoquinolium exists as a mix of 3 geometric isomers dose of 0.2mg/kg pharamodynamics: non-dep competitive block flaccid paralysis can cause histamine release - bronchospasm and hypotension pharmacokinetics A: IV, 100% BO D: large , charged, small Vd M: plasma cholinesterases , has a shorter duration of action. metabolism can be delayed by neostigmine E: metabolites renally cleared

Question 57

what is ICU acquired weakness / ventilator associated weakness?

Answer 57

common cause of morbidity from ITU admission symmetrical flaccid muscle weakness and atrophy is seen caused by prolonged stay and ventilator use. can be classed into myopathy, neuropathy or neuromyopathy risk factors include - females, older age, hyperglycaemia, sepsis, multi organ failure, malnutrition, NMBA, high dose steroids results in difficulty weaning from ventilation, ventilator associated pneumonia and VTE.

Question 58

describe the structure of rocuronium

Answer 58

aminosteroid smaller in structure than benzylisoquinoliums steroid nucleus + monoquarternary amine (allows binding to nAChR)

Question 59

tell me about rocuronium

Answer 59

Aminosteroid, non dep NMBA commonly used for paralysis in anaesthesia or RSIs found as a clear colourless solution at 10mg/ml ampoules stored at 4 degrees 10ml or 5ml. typically dose is 0.6mg/kg but in RSI 1-1.2mg/kg blocks nAChR preventing ACh binding - hence causes a flaccid paralysis Pharmacodynamics - other than this - risk of anaphylaxis - can cause a slight tachycardia pharmackinetics * A: 100% BO, IV * D: small Vd * M: hepatic metabolism * E: metabolites excreted mostly in bile (and urine)

Question 60

compare the other aminosteroids to roc

Answer 60

vec - also a mono-quarternary - presented as a powder and needs reconstituing - more potent - 0.1mg/kg - similar duration of action - favourable side effect profile - less histamine, less CVS instability - same metabolism - can be reversed by suggamadex pancuronium - bis quarternary - clear colourless solution - dose 0.1mg/kg - longer duration of action - also causes tachycardia and sympathomimetic effects.

Question 61

what factors prolong non depolarising NMBA

Answer 61

MgSO4, aminoglycosides - block VG Ca release pre-synaptically hypothermia and acidosis reduces hoffmans neostigmine increases mivacurium

Question 62

tell me about suggamadex...

Answer 62

cyclodexrin uses for the reversal of aminosteroid NMBA e.g. rocuronium and some effect of vecuronium. works via chelating - encasing them, rendering them inactive. the complex is then renally cleared found as a clear colourless solution kept at 4 degrees dose depends on its indication 2mg/kg with 2 twitches 4mg/kg with 0 twitches TOF, PTC 2 16mg/kg immediately after agent given for RSI

Question 63

how does renal failure affect suggamadex?

Answer 63

suggamadex is renally cleared therefore clearance will be reduced this has consequences on repeated use of rocuronium i.e. if patient needs to be reintubated there is also a theoretical risk the complex could dissociate and rocuronium could cause paralysis again. hence use is not recommended in those with end stage renal failure.

Question 64

what drugs interact with suggamadex?

Answer 64

progesterone and less so oestrogen hence reduces efficiacy of COCP - like missing a pill need to warn patient - need to use other form of contraception for 7 days

Question 65

what are the disadvantages of suggamadex?

Answer 65

patient disadvantages: * anaphylaxis risk * bradycardia has been observed * reduced efficacy of COCP economic: * costly

Question 66

tell me about suxamethonium..

Answer 66

depolarising NMBA traditionally used in RSI, can also be used for induction of anaesthesia without RSI and is favoured for its short duration of action. presented as clear colourless solution, in 2ml ampuloes 50mg/ml. stored at 4 degrees. usually 1-2mg/kg dose is given. structurally 2 Ach bound together so acts via binding nAChR, activating them, causing depolarisation and fasciculations but then blocking them from further activation and hence flaccid paralysis. pharmacodynamics * myalgia * hyperkalaemia - esp extra junctional , VF/VT * bradycardia esp on repeat and children * raised pressure - GI, intraocular * anaphylaxis - NAP 6 found worst of all NMBA * sux apnoea * MH pharamcokinetics * IV or IM - 100% BO * large, charged, small Vd * plasma cholinesterases to choline and succinic acid- rapid - lasts 10 mins * renal excretion of metabolites

Question 67

who is myalgia after sux more common in?

Answer 67

young females

Question 68

contraindications to sux?

Answer 68

* MH * previous anaphylxis * sux apnoea - relative * burns or spinal cord injury more than 24 hrs, less than 18 months * hyperkalaemia * severe muscle injury

Question 69

compare metabolism of cisatracurium and atracurium

Answer 69

atracurium - 45% hof, 45% ester, 10%unchanged cisatracurium - 75% hof, 15% unchanged, 10% ester however cisatracurium still produces less laudanosine because less is required as more potent.

Question 70

what is the IM dose of sux?

Answer 70

3-4mg/kg

Question 71

how long after exposure can sux apnoea be tested for?

Answer 71

should wait atleast 3 days after if the patient has recieved a transfusion then 8 weeks after

Question 72

how long is the longest time sux apnoea can last

Answer 72

up to 8 hours

Question 72

do you know any drug causes of sux apnoea?

Answer 72

neostigmine methotrexate lithium organophosphates

Question 72

once sux apnoea has been managed, how should this be delt with?

Answer 72

keep them intubated and ventilated until safe document everything explain to family genetic testing 3 days later family also need testing