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