neuromuscular blocker Flashcards
classify the neuromuscular blocking agents?
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)
what is the need for neuromuscular blockade?
intubation
optimise surgical field esp in neurosurgery/ opthalmic
fascilitates ventilation.
describe the structure and synthesis of acetylcholine..
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.
How many AchR need to be activated for muscle contraction, what are the implications?
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
how does the structure of NMBA relate to ACH?
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.
can you give examples of when AChR are up/down regulated and what are the implications of this…
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.
which conditions that cause extrajunctional receptors should depolaring blocks be avoided ?
burns >10% between 24hours - 18months old
spinal cord trauma 12 hours to 18 months
muscular dystrophies
how does myasthenia gravis effect NMBA?
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.
tell me about the Vd of NMBA
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.
what determines the termination of NMBA effects?
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
how is potency of NMBA measured and what is the implications of this?
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
how is the clinical duration of a NMBA officially measured?
time taken from injection to recovery of 25% of original twitch height.
recovery index = recovery from 25% to 75% of twitch height.
Describe the different TOF patterns seen in depolarising and non-depolarising agents…
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
what is the mechanism behind fade?
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.
when does phase 2 block occur?
prolonged exposure to sux i.e. repeated dose
or >2-5mg/kg odose
may see in sux apnoea patients after normal dose
what is the mechanism behind post tetanic stimulation?
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.
how is TOF used for intubation/ extubation guidance?
max 1 twitch for intubation
during surgery - depends on surgery
to give neostigmine = 2 or 3 twtiches
to extubate TOF more than 0.9
how is TOF ratio measured?
height of 4th twitch / height of first twitch
how can you reduce the myalgia seen with succinylcholine?
give small amount of non-depolarising agent first e.g. 0.1mg/kg roc - blocks some receptors to reduce fasciculations
or lidocaine too
what is succinylcholine apnoea?
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
how is succinylcholine apnoea managed?
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.
how is Sux Apnoea diagnosed?
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%
what is the differences in metabolism between the 2 groups of NON depolarising agents?
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
what isomers of mivacurium exist?
3 isomers = geometric
cis-cis
cis-trans
trans-trans -main one
what toxins effect the NMJ?
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)
what are the symptoms of organophosphate poisoning?
flaccid paralysis - excess Ach has depolarising block effect
cholinergic toxicity = SLUDGEM = salivation, lacrimation, urination, diarrhoea, GI cramping, emesis, miosis
which NMBAs are associated with histamine release
benzylisoquinoliums
how does sensitivity to NMBA vary between muscle groups?
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.
what reversal agents do you know?
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
what anticholinesterase inhibitors do you know?
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)
what are the side effects of anti-cholinesterase inhibitors? how is this dealt with?
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.
why is atropine not used instead of glycopyrolate with neostigmine
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.
what are the signs of inadequate reversal in recovery?
poorly sustained twitchy movements
weak cough
inability to hold head lifted
risk of aspiration and hypoxia
how can you assess NMBA reversal?
clinically - sustained head lift, size of tidal volume, grip strength, tongue protrusion
objectively - TOF
what is the tensilon test?
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.
draw a table comparing dose, potency, duration, onset and metabolism of the NMBAs.
which NMBA are used in ITU?
atracurium and cisatracurium are preffered as not reliant on renal/liver clearance
however technically risk of laudanosine building up in organ failure.
what are the properties of an ideal NMBA?
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
which agent is best in renal failure?
atracium/cisatracurium - hoffmans and ester hydrolysis
roc - has active metabolites and some renal clearance + suggamadex renally cleared
sux - hyperkalaemia risk
what are the DDIs of NMBAs?
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
how does acidaemia and hypothermia affect NMBA?
acidaemia and hypothermia - reduce breakdown via hoffmans
acidaemia - protonation of quarternary amine - increases affinity for AchR
how do electrolyte changes effect NMBA?
low Ca - less Ca for exocytosis - prolongs block
low K - hyperpolarisation - prolongs block
how does Acetylcholine activate AChR
binds at a subunit
2 must bind to activate nAChR
tell me about neostigmine
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
what anti-cholinesterase drugs are therapeutically?
neostig
pyridostigmine - treatment of MG
edrophonium =testing MG/cholinergic crisis
which organophosphates do you know and how do they work as poisons?
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.
how is organophosphate poisoning treated?
supportive
atropine
sedation and ventilation
pralidoxime - promotes hydrolysis of phosphorylated acetylcholinesterase complex
what is meant by cholinergic crisis? how is it managed?
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
tell me about plasma cholinesterase
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.
tell me about plasma cholinesterase deficiency..
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.
what is meant by post op residual curarisation?
muscle relaxant after anaesthesia
associated with airway weakness, aspiration, obstruction, apnoea, hypoxia
hence why NMB monitoring is required
classify the main NMBA in terms of duration
short duration - mivacurium, sux
medium - atracurium, roc
long - pancuronium
tell me about atracurium
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
how many isomers of atracurium exist? tell me about one of these
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
what is hoffmans degradation
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.
tell me about mivacurium
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
what is ICU acquired weakness / ventilator associated weakness?
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.
describe the structure of rocuronium
aminosteroid
smaller in structure than benzylisoquinoliums
steroid nucleus + monoquarternary amine (allows binding to nAChR)
tell me about rocuronium
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)
compare the other aminosteroids to roc
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.
what factors prolong non depolarising NMBA
MgSO4, aminoglycosides - block VG Ca release pre-synaptically
hypothermia and acidosis reduces hoffmans
neostigmine increases mivacurium
tell me about suggamadex…
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
how does renal failure affect suggamadex?
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.
what drugs interact with suggamadex?
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
what are the disadvantages of suggamadex?
patient disadvantages:
* anaphylaxis risk
* bradycardia has been observed
* reduced efficacy of COCP
economic:
* costly
tell me about suxamethonium..
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
who is myalgia after sux more common in?
young females
contraindications to sux?
- MH
- previous anaphylxis
- sux apnoea - relative
- burns or spinal cord injury more than 24 hrs, less than 18 months
- hyperkalaemia
- severe muscle injury
compare metabolism of cisatracurium and atracurium
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.
what is the IM dose of sux?
3-4mg/kg
how long after exposure can sux apnoea be tested for?
should wait atleast 3 days after
if the patient has recieved a transfusion then 8 weeks after
how long is the longest time sux apnoea can last
up to 8 hours
do you know any drug causes of sux apnoea?
neostigmine
methotrexate
lithium
organophosphates
once sux apnoea has been managed, how should this be delt with?
keep them intubated and ventilated until safe
document everything
explain to family
genetic testing 3 days later
family also need testing
